Is Correction of Iron Deficiency a New Addition to the Treatment of the Heart Failure?

Anemia is present in about 40% of heart failure (HF) patients. Iron deficiency (ID) is present in about 60% of the patients with anemia (about 24% of all HF patients) and in about 40% of patients without anemia (about 24% of all HF patients). Thus ID is present in about half the patients with HF. The ID in HF is associated with reduced iron stores in the bone marrow and the heart. ID is an independent risk factor for severity and worsening of the HF. Correction of ID with intravenous (IV) iron usually corrects both the anemia and the ID. Currently used IV iron preparations are very safe and effective in treating the ID in HF whereas little information is available on the effectiveness of oral iron. In HF IV iron correction of ID is associated with improvement in functional status, exercise capacity, quality of life and, in some studies, improvement in rate of hospitalization for HF, cardiac structure and function, and renal function. Large long-term adequately-controlled intervention studies are needed to clarify the effect of IV iron in HF. Several heart associations suggest that ID should be routinely sought for in all HF patients and corrected if present. In this paper we present our approach to diagnosis and treatment of iron deficiency in heart failure.

Correction of iron deficiency in the cardiorenal syndrome.

Impaired energy metabolism is a feature of Congestive Heart Failure (CHF). Iron deficiency has been shown to reduce energy production in the cell in animals and humans. Iron deficiency is common in both Chronic Kidney Disease (CKD) and in CHF. Recent studies suggest that iron deficiency is an independent risk factor for mortality in CHF. Studies of correction of the anemia with intravenous (IV) iron in both CKD and CHF have shown an improvement in the anemia and, in some cases, in the renal function as well. Some CHF studies of correction of the iron deficiency have shown an improvement in cardiac function and structure as well as in exercise capacity and quality of life. This occurred independent of whether or not they had anemia, suggesting that the iron deficiency itself may be independently contributing to the worsening of the CHF and CKD. If future long-term studies confirm the safety and efficacy of IV iron in the treatment of iron deficiency in CKD and CHF, this will become a new addition to the therapeutic armamentarium of the cardiorenal syndrome, and parameters of iron deficiency will become part of the routine measurements performed in both CKD and CHF whether or not the patient is anemic.

Usefulness of total lymphocyte count as predictor of outcome in patients with chronic heart failure.

Low lymphocyte count has been considered a predictive marker of unfavorable outcomes for patients with heart failure (HF). Baseline blood samples for complete blood counts, differential counts, renal function tests. and lipid profile were prospectively obtained to assess the association between lymphocyte count and clinical outcomes in 305 patients with HF (average New York Heart Association [NYHA] class 2.8). The mean follow-up duration was 4.7 years (range 8 months to 8.4 years), and 111 patients (36%) died during the follow-up period. The mean lymphocyte count for the group was 1,803.64 ± 740.3, and the mean left ventricular ejection fraction (LVEF) was 37%. Patients with low lymphocyte counts (<1,600 median count) after 8 years had significantly lower survival rates than those with lymphocyte counts ≥1,600 (58% vs 72%, p=0.012). The prediction of poorest survival was for patients in NYHA class III or IV and with lymphocyte counts <1,600. Regression analysis showed that lymphocyte level, the LVEF, and NYHA class were predictors of mortality. Of these, NYHA class was the most prominent predictor, followed by lymphocyte count, which was even more significant than the LVEF (hazard ratio 0.76, p=0.037). In conclusion, the findings of this study demonstrate that total lymphocyte count is an important prognostic factor, inversely associated with predicted mortality. Although the total low lymphocyte count was correlated with a lower NYHA class and a lower LVEF, it emerged as an independent death risk factor in patients with chronic HF.

Intravenous iron in heart failure: beyond targeting anemia.

Iron deficiency is commonly seen in congestive heart failure (CHF) in both anemic and nonanemic patients. In six studies in which these iron-deficient patients with CHF were treated with intravenous (IV) iron, five found an improvement in the hemoglobin. In uncontrolled and controlled studies, the New York Heart Association (NYHA) class, quality of life, and exercise capacity were improved consistently with IV iron. In some studies, cardiac function also was improved. In one large, double-blind, placebo-controlled study of IV iron, the patient global assessment, quality of life, and NYHA class improved rapidly in both those who were anemic or not anemic. In contrast to these studies, another controlled study of anemia in CHF showed no effect of oral iron on hemoglobin or on any cardiac parameters over 1 year. These studies suggest that CHF in both anemic and nonanemic iron-deficient patients may benefit from a course of IV iron, but not oral iron.

Anaemia management in cardio renal disease.

Anaemia is common in congestive heart failure (CHF) and is associated with increased mortality, morbidity and progressive renal failure. The common causes of the anaemia are the associated renal failure and excessive cytokine production, both of which can cause depression of the erythropoietin (EPO) production in the kidney and depression of EPO response in bone marrow. The cytokines can also induce iron deficiency by increasing hepcidin production from the liver, which both reduces gastrointestinal iron absorption and reduces iron release from iron stores located in the macrophages and hepatocytes. Attempts to control this anaemia will have to consider the use of both erythropoiesis stimulating agents (ESA) as well as oral and, probably more importantly, intravenous (IV) iron. Studies of anaemia in CHF with ESA and oral or IV iron and even with IV iron alone have shown a positive effect on hospitalisation, fatigue and shortness of breath, cardiac and renal function, quality-of-life, exercise capacity and reduced beta natriuretic peptide and have not demonstrated an increase in cardiovascular damage related to therapy. Although some studies and meta-analyses have revealed improvement in these parameters others have not. Adequately powered long-term placebo-controlled studies of ESA and of IV iron in CHF are needed and are currently being carried out.

Baseline low-density lipoprotein cholesterol levels and outcome in patients with heart failure.

The incidence of heart failure (HF) is constantly increasing in the Western world. Treatment with statins is well established for the primary and secondary prevention of cardiac events by lowering low-density lipoprotein (LDL) cholesterol levels. There are conflicting reports on the role of LDL cholesterol as an adverse prognostic predictor in patients with advanced HF. The aim of this study was to investigate the association between LDL cholesterol levels and clinical outcomes in 297 patients with severe HF (average New York Heart Association class 2.8). The mean follow-up period was 3.7 years (range 8 months to 11.5 years), and 37% of the patients died during follow-up. The mean time to first hospital admission for HF was 25 +/- 17 months. The study group was divided according to plasma LDL level < or =89, >89 to < or =115, >115 mg/dl. Patients with the highest baseline LDL cholesterol levels had significantly improved outcomes, whereas those with the lowest LDL cholesterol levels had the highest mortality. When analyzed with respect to statin use, it emerged that the negative association between LDL cholesterol level and mortality was present only in the patients with HF who were treated with statins. In conclusion, lower LDL cholesterol levels appear to predict less favorable outcomes in patients with HF, particularly those taking statins, raising questions about the need for aggressive LDL cholesterol-lowering strategy in patients with HF, regardless of its cause.

Antibodies to oxidized LDL as predictors of morbidity and mortality in patients with chronic heart failure.

BACKGROUND: Oxidative stress appears to play a significant role in the pathogenesis of heart failure (HF). Antibodies to oxidized low-density lipoprotein (Ox LDL Abs) reflect an immune response to LDL over a prolonged period and may thus represent oxidative stress over an extended time. Ox LDL Abs have been shown to correlate with clinical control in HF patients. We evaluated the predictive power of Ox LDL Abs on the outcome in patients with HF. METHODS AND RESULTS: Baseline levels of Ox LDL Abs were determined by enzyme-linked immunosorbent assay in 284 consecutive outpatients with severe chronic HF who were being treated in the cardiology services of our medical center. Their mean New York Heart Association (NYHA) Class was 2.8. The mean follow-up for the group was 3.7 years, during which 107 (37%) died. The mean time from symptom onset to first hospital admission from HF was 25.8 months. Ox LDL Abs were found to predict morbidity and mortality as evaluated by a Cox multivariate regression analysis with a hazard ration of 1.013 (P < .013), whereas N-terminal pro-B-type natriuretic peptide (NT pro-BNP) levels achieved a HR of 1.028 (P < .099). CONCLUSIONS: Ox LDL Abs level maybe a useful parameter for monitoring and planning better management of patients with HF. It was superior to pro-BNP as a predictor of clinical course as expressed by time to hospitalization.

The anemia of heart failure.

Anemia is common in congestive heart failure (CHF) and is associated with an increased mortality and morbidity. The most likely causes of anemia are chronic kidney disease (CKD) and excessive cytokine production, both of which can cause depression of erythropoietin (EPO) production and bone marrow activity. The cytokines also induce iron deficiency by both reducing gastrointestinal iron absorption and iron release from iron stores located in the macrophages and hepatocytes. Iron deficiency can cause thrombocytosis which might also contribute to cardiovascular complications in both CHF and CKD and is partially reversible with iron treatment. Thus attempts to control this anemia will have to consider both the use of erythropoiesis-stimulating agents (ESA), such as EPO, as well as oral and, probably more importantly, intravenous (IV) iron. The many studies on anemia in CHF patients treated with ESA and oral or IV iron, and even with IV iron without ESA have up to now shown a quite consistent positive effect on hospitalization, fatigue, shortness of breath, quality of life, exercise capacity, and beta-natriuretic peptide reduction, in the absence of increased cardiovascular damage related to the therapy. Adequately powered long-term placebo-controlled studies of ESA and/or IV iron are currently being carried out and their results are eagerly awaited.

Isolated ventricular non-compaction: an underdiagnosed cause of congestive heart failure.

Isolated ventricular non-compaction is a frequently underdiagnosed rare congenital cardiomyopathy. The importance of diagnosing this cardiomyopathy lies especially in asymptomatic patients, screening relatives of index cases in order to focus on their follow-up, and searching for criteria warranting prophylactic anticoagulation, implantable cardioverter defibrillator and anti-remodeling drugs such as angiotensin-converting inhibitors. We present the clinical and imaging characteristics of this entity and discuss some of the therapeutic dilemmas involving these patients.

The correction of anemia in patients with the combination of chronic kidney disease and congestive heart failure may prevent progression of both conditions.

It has recently been recognized that many patients with congestive heart failure (CHF) are anemic. The anemia is very often associated with chronic kidney disease (CKD). The more severe the anemia the more severe the CHF, with higher mortality, morbidity, and hospitalization rate. The only way to prove that the anemia is itself a causative factor in the progression of both the CKD and the CHF is to correct it. In this paper we review the results of published papers and some preliminary reports about correction of this anemia in CHF. These studies frequently showed that erythropoietic stimulating agents (ESA) with oral or IV iron often resulted in improvement in left ventricular systolic and diastolic function, dilation, and hypertrophy, stabilization or improvement in renal function, reduced hospitalizations, diuretic dose, mitral regurgitation, pulmonary artery pressure, plasma volume, heart rate, serum brain natriuretic peptide levels, and the inflammatory markers C reactive protein and Interleukin 6, and an improvement in New York Heart Association class, exercise capacity, oxygen utilization during exercise, sleep apnea, caloric intake, depression, and quality of life. The activity of endothelial progenitor cells was also increased. Iron deficiency may also play an important role in the anemia, because significant improvement of cardiac, renal, and functional status in these anemic CKD-CHF has been seen after treatment with IV iron alone. Clearly more work is needed to clarify the relationship between anemia, CKD and CHF.

Circulating apoptotic progenitor cells in patients with congestive heart failure.

BACKGROUND: Circulating CD34+ endothelial progenitor cells (EPCs) are capable of differentiating into mature endothelial cells to assist in angiogenesis and vasculogenesis. We sought to quantify the numbers of apoptotic progenitors in patients with congestive heart failure. METHODS AND RESULTS: Peripheral blood mononuclear cells were isolated by Ficoll density-gradient from 58 patients with various degrees of heart failure and 23 matched controls. Apoptosis in progenitor CD34+ cells was assessed using the Annexin V-PE/PI detection kit, and FACS analysis was performed with triple staining for CD34, annexin-V and propidium iodide. The percentage of early and late apoptotic progenitor cells was determined in the subject groups and was correlated with clinical characteristics. While there was no significant difference in total CD34 positive cells or early apoptotic progenitors between control subjects and CHF patients (p = 0.42) or between severe and mild/moderate CHF groups (p = 0.544), there was an elevated number of late apoptotic progenitors in the severe CHF group compared with the mild/moderate CHF group (p = 0.03). Late apoptotic progenitors were significantly increased in CHF patients as compared to matched controls. There was also an inverse correlation between late apoptotic progenitors and ejection fraction (r = -0.252, p = 0.028) as well as a positive association with NYHA class (r = 0.223, p = 0.046). CONCLUSION: Severe heart failure patients exhibited higher numbers of late apoptotic progenitors, and this was positively associated with NYHA class and negatively correlated with ejection fraction. This finding may shed light on the numerous factors governing the pathophysiology of CHF.

The role of correction of anaemia in patients with congestive heart failure: a short review.

Many patients with Congestive Heart Failure (CHF) are anaemic. This anaemia is associated with more severe CHF and a higher incidence of mortality, hospitalisation and morbidity. The only way to prove that the anaemia is causing this worsening of CHF is to correct it. We review here some of the published papers about correction of anaemia. Many studies show a positive effect of Erythropoietin (EPO) or its' derivatives when administered in combination with oral or IV iron, with improvements in left and right ventricular systolic and diastolic function, dilation and hypertrophy and renal function. In addition, a reduction in hospitalisations, diuretic dose, pulmonary artery pressure, plasma volume, heart rate, serum Brain Natriuretic Peptide levels, the inflammatory marker Interleukin 6, soluble Fas ligand--a mediator of apoptosis, and improvements in New York Heart Association class, exercise capacity, oxygen utilization, caloric intake, Quality of Life and the activity of Endothelial Progenitor Cells, have been observed. Iron deficiency may also play an important role in this anaemia, since improvements in CHF have also been reported following treatment with IV iron alone. However, until the ongoing large placebo-controlled studies of the EPO derivative darbepoetin or IV iron are completed, we will not know whether these treatments really influence CHF outcome.

Usefulness of serum myeloperoxidase in prediction of mortality in patients with severe heart failure.

BACKGROUND: Myeloperoxidase levels were shown to reflect endothelial dysfunction, inflammation, atherosclerosis and oxidative stress. OBJECTIVES: To examine the role of circulating myeloperoxidase, a leukocyte-derived enzyme, as a predictor of mortality in patients with congestive heart failure. METHODS: Baseline serum MPO levels were measured in 285 consecutive CHF patients and 35 healthy volunteers. N-terminal pro-brain natriuretic peptide and high sensitivity C-reactive protein concentrations were also measured. The primary outcome endpoint was overall mortality. RESULTS: MPO levels were significantly elevated in patients with CHF compared to healthy volunteers (P = 0.01). During a mean follow-up of 40.9 +/- 11.3 months there were 106 deaths. On a univariate Cox regression analysis MPO levels were of marginal value (P = 0.07) whereas NT-proBNP was of considerable value (P < 0.0001) in predicting all-cause mortality. By dividing our cohort according to NT-proBNP levels into high, intermediate and low risk groups a clear difference in mortality was shown. By further dividing the patient cohort according to MPO levels above or below the median (122.5 ng/ml), mortality prediction improved in the patients with intermediate NT-proBNP values. CONCLUSIONS: MPO levels are elevated in CHF and correlate with disease severity. MPO has an additive predictive value on mortality in patients with intermediate NT-proBNP levels.

Predictive value of high sensitivity CRP in patients with diastolic heart failure.

BACKGROUND: C-reactive protein (CRP) has been tested in patients with systolic heart failure (HF) and mixed results have been obtained with regards to its potential predictive value. However, the role of C-reactive protein (CRP) in patients with diastolic HF is not established. We studied the predictive role of high sensitivity CRP (hsCRP) in patients with diastolic HF. METHODS: HsCRP levels were measured in a cohort of CHF outpatients, 77 patients with diastolic HF and 217 patients with systolic HF. Concentrations were compared to a large cohort of healthy population (n=7701) and associated with the HF admissions and mortality of the patients. RESULTS: Levels of hsCRP did not differ between patients with systolic and diastolic HF and were significantly elevated compared to the cohort of healthy subjects even after adjustment to various clinical parameters (p<0.0001). In patients with diastolic HF, hsCRP levels associated with New York Heart Association functional class (NYHA-FC) (r=0.31 p=0.01). On univariate Cox regression model hsCRP levels independently predicted hospitalizations in patients with systolic but not diastolic HF (p=0.047). CONCLUSION: HsCRP concentrations are elevated in patients with diastolic HF and correlate with disease severity; their prognostic value in this patient population should be further investigated.

Improvement of anemia with erythropoietin and intravenous iron reduces sleep-related breathing disorders and improves daytime sleepiness in anemic patients with congestive heart failure.

BACKGROUND: Central sleep apnea (CSA) (with or without Cheyne-Stokes breathing) or obstructive sleep apnea (OSA) are common in congestive heart failure (CHF). Correction of anemia may improve CHF. We hypothesized that correction of anemia might also improve sleep-related breathing disorders (SRBDs) in CHF. METHODS: Thirty-eight patients with CHF and anemia (hemoglobin level < 12 g/dL) were treated with erythropoietin and intravenous iron to a target hemoglobin level of 13 g/dL. Home sleep recordings were done before and after 3 months of treatment. RESULTS: Thirty-seven patients had SRBD (Apnea Hypopnea Index [AHI] of > or = 10). Hemoglobin level increased from 10.4 +/- 0.8 to 12.3 +/- 1.2 g/dL (P < .001). Total AHI values decreased from 35.9 +/- 12.2 to 24.9 +/- 12.2 (P < .001). The AHI of CSA, OSA and Cheyne-Stokes breathing decreased from 26.5 +/- 14.6 to 18.6 +/- 7.7, from 9.4 +/- 10.9 to 6.9 +/- 9.8, and from 13.1 +/- 16.4 to 9.0 +/- 12.2, respectively (all P < .05). Sleep minimal oxygen saturation (SaO2) increased from 62% +/- 12% to 71% +/- 11%; Epworth Sleepiness Scale score improved from 9.4 +/- 6.2 to 6.0 +/- 5.0 and New York Heart Association class improved from 2.9 +/- 0.4 to 1.7 +/- 0.7, all P < .001. Hemoglobin level improvement correlated with improvement in OSA+CSA, CSA, minimal SaO2, Epworth Sleepiness Scale score, and New York Heart Association class (all P < .001). CONCLUSION: Improvement of anemia in CHF is associated with a reduction in SRBD and an improvement in daytime sleepiness.

Circulating endothelial progenitor cells and clinical outcome in patients with congestive heart failure.

BACKGROUND: Circulating endothelial progenitor cells (EPCs) are increased in conditions associated with ischaemia and can potentially support angiogenesis and vasculogenesis. EPC levels were also shown to predict outcome in patients with atherosclerotic vascular disease. We tested the hypothesis that circulating EPC can predict outcome in patients with congestive heart failure (CHF). METHODS: EPC-colony-forming units were measured in the peripheral blood of 107 consecutive patients with CHF with New York Heart Association (NYHA) functional class II-IV. Serum levels of vascular endothelial growth factor (VEGF), N-terminal pro-B-type natriuretic peptide (NT-pro-BNP) and high-sensitivity C-reactive protein (hsCRP) were also measured. End points were defined as CHF-related hospital admissions and all-cause mortality. RESULTS: Age (p = 0.01), diabetes mellitus (p = 0.002) and EPC levels (p = 0.02) were found to be independent predictors of all-cause mortality. EPC levels did not predict CHF-related hospitalisations. EPC levels correlated positively with NYHA (p = 0.05, r = 0.19), but did not correlate with VEGF, NT-pro-BNP or hsCRP. EPC levels did not differ by the aetiology of CHF. CONCLUSIONS: EPC levels are independent predictors of all-cause mortality among patients with CHF.