Low blood pressure anemia

Contents

Anemia in chronic kidney disease

Are you at risk for anemia?

Take our short quiz to learn more about the symptoms of anemia.

There’s more to chronic kidney disease than you think…

If your kidneys are not working properly, they may not be able to help your body make the red blood cells it needs. Anemia is a common side effect of kidney disease.

  • What causes anemia?
  • How does chronic kidney disease (CKD) cause anemia?
  • What are the symptoms of anemia?
  • Causes of anemia in CKD
  • How will I know if I have anemia?
  • How is anemia treated?
  • Anemia and end-stage renal disease (ESRD)
  • Talk with your doctor about anemia
  • Resources for professionals
  • Resources for patients

What causes anemia?

Anemia happens when there are not enough red blood cells in your body.

Red blood cells carry oxygen through your bloodstream, giving you energy and helping your muscles, bones, and organs work properly.


  • Normal

    The oxygen that we breathe in passes through our lungs and into the red blood cells.


  • Anemia

    In anemia, there are not enough red blood cells to carry this oxygen around the body.

Anemia can make you feel weak and tired because you are not getting the energy you need.

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How does chronic kidney disease (CKD) cause anemia?

Anybody can develop anemia, but it is very common in people with CKD. People with CKD may start to have anemia in the early stages of CKD, and anemia usually gets worse as CKD gets worse. If your kidneys are not working as well as they should, you are more likely to get anemia.

Anemia in CKD is more common if you:


  • Have diabetes


  • Have heart disease


  • Have high blood pressure


  • Are African-American


  • Are older than 75 years

If you think you might be at risk, talk to your doctor about getting tested. Management of anemia and its symptoms may help you feel better.

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What are the symptoms of anemia?

Anemia can happen with or without symptoms. Many of the symptoms of anemia can also be caused by other problems. The only way be sure if you have anemia is to get tested. If you are experiencing symptoms, it is important that you talk to your doctor.


  • Dizziness, loss of concentration

    Feeling dizzy or having difficulty concentrating may be a sign that your brain is not getting enough oxygen.

  • Pale skin

    Paleness is caused by reduced blood flow or a lower number of red blood cells.

  • Chest pain

    Anemia in CKD can increase your risk of heart problems because the heart has to work harder to provide blood to your body. If you experience an unusually fast heart rate or are worried about your heart health, please speak to your doctor.

  • Shortness of breath

    Your blood may not have enough red blood cells to deliver oxygen to your muscles. By increasing your breathing rate, your body is trying to bring more oxygen into your body.

  • Fatigue or weakness

    Easy fatigue, loss of energy, and reduced physical capacity

  • Cold intolerence

    Sensitivity to the cold may mean there is not enough oxygen being delivered in the blood to your body

Take our short quiz to learn more about the symptoms of anemia.

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Causes of anemia in CKD

There are two main causes of anemia in CKD:

CKD and erythropoietin

All of the cells in your body live for a certain amount of time and then die. Your body is always working to make new cells to replace the ones that have died. Red blood cells live for about 115 days. Your kidneys help your body make red blood cells.

Healthy kidneys make a hormone called erythropoietin (EPO). EPO sends a signal to the body to make more red blood cells. If your kidneys are not working as well as they should, they can’t make enough EPO. Without enough EPO, your body doesn’t know to make enough red blood cells. This means fewer red blood cells are available for carrying oxygen through your body.

Healthy kidney:

  • Healthy kidney

  • Normal EPO

  • Normal number of red blood cells

CKD

  • Chronic Kidney Disease

  • Reduced EPO

  • Reduced number of red blood cells

CKD and iron

Iron is a mineral found in many foods, such as meats and leafy greens. Your body uses iron to make red blood cells. A common cause of anemia in people with CKD is iron deficiency. Iron deficiency means you do not have enough iron in your body. It can be caused by not getting enough iron in your diet or by losing blood, either through blood tests or during dialysis. If you don’t take in enough iron through your diet, you can get anemia. Around half of people with CKD stages 2 to 5 have some kind of iron deficiency.

Causes of iron deficiency

  • Not eating enough foods that are rich in iron

  • Iron from your food is not being absorbed properly into your bloodstream

  • Frequent blood donation or testing may increase demand for iron

  • Blood loss from dialysis

Other kinds of anemia

There are several kinds of anemia. Anemia caused by having too little EPO or too little iron in your body are the most common in people with CKD. Talk to your doctor to learn more.

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How will I know if I have anemia?

Talk to your doctor if you think you may have anemia. The only way to know if you have anemia is to have a blood test. When you have kidney disease, your doctor will want you to have blood tests often. These tests are used to check not only your kidney function, but also for signs of any other problems, such as the number of red blood cells and how much iron you have in your body.

The test for anemia is a simple blood test to check for the amount of hemoglobin in your blood. Hemoglobin is a part of your red blood cells. Figuring out the amount of hemoglobin you have in your blood can tell your doctor how many red blood cells you have.

Your doctor may also ask you if you’ve noticed any symptoms, such as changes in skin color or feeling unusually tired.

Take our short quiz to learn more about the symptoms of anemia.

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How is anemia treated?

Getting your anemia treated can help you feel better. Depending on the cause of your anemia, your doctor may recommend one of the following treatments:

  • Erythropoiesis-stimulating agents (ESAs) — ESAs are medicines that work by sending a signal to the your body to make more red blood cells.
  • Iron supplements — Your doctor may give you iron supplements as pills or as a shot. If you are on dialysis, you may be given an iron supplement during your dialysis treatment.
  • Red blood cell transfusion — A red blood cell transfusion is a procedure to increase the number of red blood cells in your body by giving you red blood cells from someone else’s body through an IV. This can temporarily improve your anemia symptoms.

Doctors and researchers are working on potential new treatments for anemia. New treatments in development are tested in clinical trials. If you’re interested in joining a clinical trial to try an investigational new treatment for anemia, visit ClinicalTrials.gov to learn about all available clinical trials for anemia.

If you have CKD, getting early treatment for your anemia can help slow the progress of your CKD. If you think you might have anemia, talk to your doctor about getting tested.

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Anemia and end-stage renal disease (ESRD)

Anemia and end-stage renal disease (ESRD), also known as kidney failure, often go hand in hand. Most people with kidney failure who are on dialysis have anemia. Kidney transplant patients are also at higher risk for anemia. Learn more.

Click here to download a copy of the Anemia in ESRD booklet.

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Talk with your doctor about anemia

Talk with your doctor or another member of your health care team to find out more about your anemia symptoms and treatment options. Our Talk to Your Doctor Guide can help you get the conversation started.

To get your guide, click “Get started” and just fill out our quick 7-question symptom survey.

Note: This survey is not a medical diagnosis. This guide is an awareness tool designed for you and your doctor to use together. The information you provide is anonymous and will not shared.

Get started

Question 1 of 7

How often do you feel tired and/or weak and don’t know why? Not often Sometimes Often How much does that bother you? Not at all A little A lot

Question 2 of 7

How often do you notice your heart beating faster than normal? Not often Sometimes Often How much does that bother you? Not at all A little A lot

Question 3 of 7

How often do you have trouble breathing or catching your breath? Not often Sometimes Often How much does that bother you? Not at all A little A lot

Question 4 of 7

How often do you feel dizzy? Not often Sometimes Often How much does that bother you? Not at all A little A lot

Question 5 of 7

How often do you have trouble concentrating? Not often Sometimes Often How much does that bother you? Not at all A little A lot

Question 6 of 7

How often do you feel cold when others do not? Not often Sometimes Often How much does that bother you? Not at all A little A lot

Question 7 of 7

Does your skin look unusually pale or dull? Not often Sometimes Often How much does that bother you? Not at all A little A lot

Download your printable Doctor Conversation Guide. Remember to show it to your doctor!

Download (PDF)

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If you are having trouble, please visit this page on a desktop computer for access to the PDF.

Learn more about anemia and chronic kidney disease and receive updates from the American Kidney Fund.

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Resources for professionals

The ACT on Anemia campaign is helping health care professionals have conversations with their patients about the link between chronic kidney disease and anemia.

Online courses with free CEs for professionals

Talk to your patient guide

View the doctor conversation guide video

Gain insights from our kidney disease and anemia survey

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Resources for patients

Download the tools you need to learn more about the connection between chronic kidney disease and anemia. Use these materials to start a conversation during your next health care appointment.

ACT on Anemia CKD booklet

ACT on Anemia ESRD booklet

Talk to your doctor guide

Risk identifier quiz

View your doctor conversation guide video

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Anemia and Your Heart

Anemia is a blood condition in which the levels of hemoglobin (an essential protein that carries oxygen to your tissues and organs) are lower than normal.

Anemia usually occurs when you don’t have enough red blood cells — the cells that transport hemoglobin throughout your body.

In other instances, the red blood themselves may simply contain too little hemoglobin.

How Anemia Affects Your Health

When someone is anemic, the body doesn’t get the oxygen that it needs. If anemia is unrecognized and untreated, serious damage can occur in the organs.

Symptoms of anemia include:

  • Generalized weakness
  • Fatigue
  • Difficulty catching your breath
  • Chest pain or discomfort
  • Fast or abnormal heartbeat
  • Feeling cold all the time, especially in the hands and feet
  • Numbness in the hands and feet
  • Pale appearance
  • Irritable mood
  • Problems concentrating or performing at your job or in class
  • Frequent headaches or dizziness

When anemia becomes severe, the heart has to pump harder and faster to compensate for the decreased oxygen levels in the body.

What Causes Anemia?

While there are different types of anemia, they all are due to the same underlying problems — insufficient red blood cells or lack of hemoglobin.

Common causes of anemia include:

  • Insufficient iron in the blood
  • An inherited blood condition
  • Lack of vitamins like B-12 and folate
  • Another illness (like kidney disease or cancer)
  • Rapid blood loss (due to recent surgery, heavy periods, or a bleeding ulcer)

Different Types of Anemia

The five most common forms of anemia are:

  • Iron-deficiency anemia. The most frequently diagnosed form of anemia, iron deficiency anemia is due to a lack of iron, which isIron is critical for the body’s production of hemoglobin.
  • Sickle cell anemia. This is an inherited condition in which red blood cells are misshapen, or “sickle” shaped. The abnormal shape of the red blood cells causes them to be more fragile and less effective at delivering oxygen to the tissues.
  • Thalassemia. A genetic disorder that runs in families. In thalassemia, the body doesn’t make enough red blood cells or hemoglobin.
  • Megaloblastic anemia. Megaloblastic red blood cells are produced when the body doesn’t get enough vitamin B12 or folate. These red blood cells are bigger than normal cells, but do not transport hemoglobin as efficiently.
  • Hemolytic anemia. In this condition, red blood cells are rapidly removed from the bloodstream. Infections, medications, and diseases of the immune system can all lead to this type of anemia. Hemolytic anemia can also occur after blood transfusions.

Are You At Risk for Anemia?

A number of risk factors increase the likelihood of developing anemia, including:

  • Family history of anemia or other blood disorders
  • Poor diet
  • Loss of blood following surgery or injury, or blood loss from heavy menstruation
  • Chronic illness, including diabetes, cancer, HIV/AIDS, inflammatory bowel disease, thyroid problems, and kidney disease

Anemia‘s Impact on Heart Health

The link between anemia and heart disease is clear: Up to 48 percent of people who have had heart failure are anemic. And of people hospitalized for a heart attack, 43 percent were found to have anemia. People who are anemic are at a 41-percent greater risk of having a heart attack or needing procedures to treat heart disease as compared to those without anemia.

When left untreated, anemia takes a toll on the body — particularly the heart — because oxygen levels are chronically diminished. People who already have heart disease may actually worsen their condition if they also develop anemia because decreased oxygen places added strain on the heart.

Diagnosing, Treating, and Preventing Anemia

Several simple blood tests can be used to diagnose anemia. Your doctor will perform a complete blood count (CBC) to determine how much hemoglobin there is in your blood. A CBC is also useful because it shows whether your other blood cell levels (white blood cells and platelets) are low. This information can help your doctor identify the source of your anemia. Iron, vitamin B12, and folate levels are also usually checked in the process of diagnosing anemia.

If your doctor thinks that you might have an inherited form of anemia, a special test called hemoglobin electrophoresis may also be performed. This test reveals the specific types of hemoglobin in your blood and can help diagnose conditions such as sickle cell anemia and thalassemia.

After anemia is diagnosed, treatment usually begins with dietary changes, vitamin supplements (including iron, vitamin B12, and folate), and medications designed to increase red blood cell production. In some cases, procedures like a blood transfusion or bone marrow transplant may also be considered.

It’s sometimes possible to prevent anemia, particularly the forms that are caused by vitamin deficiencies. Here are some tips to help decrease your risk of anemia:

  • Eat foods rich in iron like spinach, lean red meats, beans, lentils, iron-fortified cereal and bread, liver, oysters, tofu, fish, and dried fruit.
  • Get lots of vitamin C to help your body absorb iron more effectively.
  • Skip coffee and tea with your meals since they can interfere with iron absorption.

Finally, if you experience symptoms of anemia or have risk factors for anemia, talk to your doctor about getting regular screening tests to check your hemoglobin and red blood cell count. Early diagnosis and prevention of anemia will not only help you feel better faster, but it will also improve your heart health.

Anemia in Heart Failure Patients

Abstract

Heart failure is a very common disease, with severe morbidity and mortality, and a frequent reason of hospitalization. Anemia and a concurrent renal impairment are two major risk factors contributing to the severity of the outcome and consist of the cardio renal anemia syndrome. Anemia in heart failure is complex and multifactorial. Hemodilution, absolute or functional iron deficiency, activation of the inflammatory cascade, and impaired erythropoietin production and activity are some pathophysiological mechanisms involved in anemia of the heart failure. Furthermore other concomitant causes of anemia, such as myelodysplastic syndrome and chemotherapy, may worsen the outcome. Based on the pathophysiology of cardiac anemia, there are several therapeutic options that may improve hemoglobin levels, tissues’ oxygenation, and probably the outcome. These include administration of iron, erythropoiesis-stimulating agents, and blood transfusions but still the evidence provided for their use remains limited.

1. Introduction

Cardiovascular diseases are among the most frequent causes of death worldwide . Heart failure is an enormous medical and societal burden and a leading cause of hospitalization. It is estimated that 2.6 millions hospitalizations annually in the USA are due to heart failure as a primary or secondary diagnosis .

In the last 19 years the role of several immunological, metabolic, and neurohormonal abnormalities has been recognized in the pathophysiology and progression of the congestive heart failure (CHF) . Among them, anemia and renal failure seem to be major risk factors for an adverse outcome. The cardio renal anemia syndrome (CRAS) represents a pathological triangle in which the primary failing organ is the heart or the kidney and the dysfunction of one organ leads to dysfunction of the other . The presence of anemia or renal dysfunction increases morbidity and mortality in patients with heart failure. It seems that there is an impaired mechanism operating between congestive heart failure, chronic kidney disease (CKD), and anemia, where each might cause or worsen the other. Therefore, correction of anemia would be a major part of this vicious circle in the reduction of the severity of the heart failure . This could be explained by the fact that a significant feature of the congestive heart failure is impaired energy metabolism and therefore the failing heart is an energy-starved heart . Oxygen delivery through hemoglobin (Hb) is essential for energy production and improvement of Hb levels could also improve energy production in cardiomyocytes. Simultaneously energy-sparing treatments may also improve the prognosis .

2. Epidemiology of Anemia in Heart Failure

Using the historical definition by the World Health Organization, anemia is defined when Hb concentration is less than 13 g/dL for men or less than 12 g/dL for women . However, particularly in the setting of heart failure, this definition has not been subjected to rigorous clinical validation and its appropriateness and clinical applicability continues to be debated . Therefore, some investigators use more conservative definitions (e.g., <12 g/dL for men and <11 g/dL for women) to ensure a higher confidence in capturing the affecting population .

Anemia is prevalent in patients with CHF but the exact rates vary widely . A recent meta-analysis of 153,180 patients with CHF, reported in 34 published studies from 2001 to 2007, estimated the prevalence of anemia to be 37.2% (10–49%) . Similarly, the latest prospective STAMINA-HFP (Study of Anemia in a Heart Failure Population) Registry estimated a prevalence of 34% . The variability in the estimated prevalence of anemia is partly attributable to use of different definitions of anemia, whereas patients in the acute decompensated states experience more dilutional anemia and therefore the prevalence may be increased. Patients with CHF and anemia tend to be older than their nonanemic counterparts , whereas, in patients less than 55 years, the age of anemic and nonanemic patients does not appear to differ . Concerning the gender, in studies of CHF and anemia enrolling a preponderance of men, the proportion of women steadily increases as Hb concentration falls to the point that women can predominate among patients with CHF and severe anemia .

One of the most frequent comorbid conditions in patients with CHF is CKD (as defined by an estimated glomerular filtration rate (eGFR) <90 mL/min−1/1.72 m−2). CHF and CKD share some common causes (e.g., hypertension), features (e.g., malnutrition, impaired performance status), and risk factors (e.g., older age). In a meta-analysis of 16 studies, it was found that 63% of 80,098 patients with CHF had some degree of concomitant impaired renal function and 29% of them had severe CKD. This is associated with an increased risk of adverse outcome , being probably a stronger predictor of mortality than ejection fraction (EF) or New York Heart Association (NYHA) functional classes . Anemia is more prevalent when CHF and CKD coexist in both ambulatory and hospitalized settings . In large CHF registries the degree of anemia closely parallels to eGFR, although primary renal disease is relatively uncommon in CHF . This justifies that kidneys play a major role in the pathophysiology of anemia in CHF. It is important that patients with CHF and CKD develop anemia in higher values of eGFR than patients with CKD alone. This provides indirect evidence that other factors than CKD are involved in the pathophysiology of anemia of CHF .

Anemia exacerbates symptoms of heart failure. There is an impaired mechanism in which tissue hypoxia and release of nitric oxide (NO) cause decreased arteriolar resistance and peripheral vasodilatation. These in turn lead to decreased blood pressure, increased sympathetic activation, renal vasoconstriction, reduced renal function, and activation of renin-angiotensin aldosterone system. The results are production of antidiuretic hormone, fluid retention, left ventricular (LV) hypertrophy and dilation, worsening of heart failure, release of brain natriuretic peptide (BNP), and signs from stress on myocardium. The final outcome, completing the vicious circle, is further anemia. This, however, implies that in the presence of volume overload there might be a decrease in Hb concentration and also oxygen content, although red cell mass remains stable . The patient complains of shortness of breath, tachycardia, dizziness, faintness, and fatigue. Therefore, the presence of anemia is tightly linked to clinical severity of CHF. Symptomatic deterioration and fluid retention inevitably lead to hospitalization. Thus, there is a greater prevalence of anemia in hospitalized patients than ambulatory ones . On the other hand, the presence of more advanced NYHA functional classes has been associated with greater prevalence of anemia . Furthermore, anemic patients with CHF have more commonly diabetes mellitus and more advance disease, with higher NYHA class and more severe symptoms. Those symptoms include lower exercise capacity, worse quality-of-life scores, greater peripheral edema, lower dry weight and blood pressure, higher use of diuretics and other cardiovascular medications, and worse neurohormonal profile (such as renal dysfunction, high BNP and C-reactive protein, low serum albumin) (range, 30% to 61% versus range, 4% to 23% for less symptomatic ambulatory patients) . It is remarkable that anemia does not seem to be related to LV dysfunction, whereas in few studies Hb levels were inversely related to EF. That means that patients with lower values of Hb had higher EF, whereas increase of Hb could decrease LVEF, especially in CKD, in a dose-dependent manner .

Finally, most studies indicate that the prevalence of anemia is increased in patients with CHF who also have co-morbid kidney disease, advanced age, and more severe symptoms when compared to less symptomatic ambulatory populations .

3. Pathophysiology of Anemia in Heart Failure

The major factors contributing to CHF-related anemia involve CKD, renin-angiotensin system, hematinic abnormalities, mainly iron deficiency, chronic inflammation, and hemodilution (Figure 1).


Figure 1
Pathophysiological mechanisms contributing to anemia in chronic heart failure patients. (RAAS: renin-angiotensin-aldosterone system, IL-6: interleukin-6, TNF-α: tumor necrosis factor alpha, EPO: erythropoietin, RBC: red blood cells).

A major factor contributing to anemia of CHF is kidney dysfunction, being associated with the cardiac disorder. The renal damage in the CHF is mainly hypoxic, due to reduced renal flow, caused by the reduced cardiac output . Hypoxia induces erythropoietin (EPO) production by peritubular fibroblasts, although renal blood flow in CHF is relatively maintained until the late stages of the syndrome, especially when receiving angiotensin-converting enzyme (ACE) inhibition. Nevertheless, EPO production does not seem to correlate with effective renal plasma flow. It only correlates weakly with eGFR. This suggests that renal dysfunction plays a role in the blunted EPO production in anemic patients with CHF , resulting in increased EPO levels but not as expected for the degree of anemia, suggesting that in CHF there is both blunted EPO production and resistance to EPO . Furthermore, the coexistence of CHF with CKD is associated with reduced EPO production from the kidney , as well as with urinary losses of serum EPO and transferrin , which further deteriorate the anemia.

The renin-angiotensin system seems also to be involved in the control of erythropoiesis. Angiotensin II reduces renal blood flow, increases the oxygen demands, and thereby stimulates EPO production . It also stimulates the proliferation of normal bone marrow early erythroid progenitors in a direct manner . Both ACE inhibition and angiotensin receptor blockade decrease erythropoiesis, causing a modest reduction in Hb, up to 0.3 g/dL . This suppression is attributed to a mild reduction of EPO production and also to prevention of hematopoiesis inhibitor N-acetyl-seryl-aspartyl-lysyl-proline (AcSDKP) breakdown. AcSDKP is normally degraded by the amino terminal catalytic domain of ACE. ACE inhibition should be expected to cause a mild reduction of erythropoiesis, although various knockout mice models, involving different ACE components, do not support this theory .

Iron deficiency is common in patients with CHF especially when accompanied by CKD , whereas vitamin B12 and folic acid deficiencies or iron overload are not. It is of interest that the incidence of iron deficiency is increasing with the severity of heart failure . In half cases, iron deficiency is absolute (with low transferrin saturation and serum ferritin, usually associated with decreased iron stores and reduced iron deposits in the bone marrow). In the other half cases iron deficiency is functional-relative (with low transferrin saturation and normal or elevated serum ferritin, usually associated with normal or elevated iron stores and iron deposits in the bone marrow) . It has been reported that in 17% of anemic patients with CHF the iron deficiency is both absolute and functional .

There are many causes of absolute iron deficiency associated with CHF, especially in coexistence with CKD. These include(1)low iron intake (due to low protein diets and anorexia),(2)gastrointestinal blood loss (due to platelet dysfunction or coagulation abnormalities; caused by platelet inhibitors, anticoagulants, or uremia),(3)iron malabsorption (due to either CHF or uremia related-bowel edema, causing intestinal cell dysfunction, or to proton pump inhibitors or to phosphate binders, that also bind iron), (4)removal of blood for tests.

In CHF the functional iron deficiency is related to iron disuse, resembling anemia of chronic disease, as evidenced by iron acquisition by the reticuloendothelial system . In patients with severe CHF, elevation of several inflammatory cytokines serum levels has been found. Among them, interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and less frequently interleukin-18 (IL-18) seem to be the most important, whereas IL-6-induced hepcidin expression also participates in the phenomenon . This inflammatory process causes reduced EPO production, through activation of GATA 2 binding protein and nuclear factor-κB, and impaired response to bone marrow erythroblasts. It also causes hepcidin-induced blockade of iron absorption from the gut and iron trapping in reticuloendothelial system’s stores. Hepcidin is an acute phase antibacterial protein, induced by IL-6, through JAK/Stat3 pathway, released from the liver and excreted from the urine. Therefore, in CHF with a concomitant CKD, there is a reduced hepcidin removal from the kidney, implying a further increase of its levels. Hepcidin inhibits ferroportin, a protein expressed on intestinal cells, macrophages, and hepatocytes that releases the iron from those cells into the blood. Hepcidin-induced inhibition of ferroportin causes decreased iron absorption from the gut and blockade of iron release from its stores, in hepatocytes and macrophages, into the blood. This implies inadequate iron delivery to the bone marrow erythroblasts, although the total stores may be adequate, causing a functional iron deficiency. Furthermore hepcidin seems to exert a direct inhibitory effect on erythroblast proliferation and survival .

Iron metabolism is crucial for energy production in the body and most importantly for cells with high energy demands, such as cardiomyocytes . Iron plays a crucial role in oxygen transportation (as a component of Hb), oxygen storage (as a component of myoglobin), oxidative metabolism (as a component of oxidative enzymes and respiratory chain processes), and in metabolism of lipids, carbohydrates, nucleic acids, collagen, tyrosine, and catecholamines . In CHF, an energy-starved situation, several disorders of iron metabolism have been observed. Iron deficiency, absolute or functional, can impair oxidative metabolism, cellular energetic, and cellular immune mechanisms. Iron deficiency in rat hearts causes mitochondrial ultrastructural aberrations, irregular sarcomere organization, and release of cytochrome C . In addition, experimental animal models with severe iron deficiency have major disruption in energy production causing cardiac damage, with diastolic dysfunction and heart failure, accompanied by reduced EPO and increased TNF-α serum levels and worsening of molecular signaling pathways. Those defects may participate in the transition from adaptive cardiac hypertrophy to permanent cardiac impairment in chronic iron deficiency . On the other hand, iron seems to have anti-inflammatory effects. It has been shown that hemodialysis patients receiving EPO with IV iron supplementation had lower inflammation markers (lower levels of proinflammatory TNF-α and free radicals, as expressed by total peroxides, and higher levels of anti-inflammatory interleukin-4) compared to patients receiving EPO alone . Furthermore iron deficiency anemia seems to enhance red cell oxidative stress and has been associated with lower peak oxygen consumption and higher ratios of ventilation to carbon dioxide production . In a recent study the disordered iron homeostasis has been identified as an independent risk factor for death .

Another effect of iron deficiency on CHF patients is the consequent thrombocytosis. CHF is a hypercoagulable state , where the co-existence with iron deficiency-related thrombocytosis increases the risk of thrombosis and the mortality rate . Furthermore, it has been shown that the concomitant administration of IV iron with EPO (which can cause iron deficiency) in hemodialysis patients significantly reduces the platelet counts, compared to patient receiving EPO alone . It has also been shown that the use of erythropoiesis-stimulating agents (ESAs) in iron-deficient patients increases the risk of thrombocytosis and thrombosis .

Except iron disuse, inflammatory cytokines may cause EPO resistance in anemic CHF patients. It has been suggested that there is a diminished responsiveness of erythroid cells to EPO, being accompanied by increased levels of inflammatory cytokines, such as IL-6, soluble TNF receptor 2, and TNF-α levels . Their activation does not result in EPO receptor downregulation, but in blunted EPO-induced JAK-STAT signaling . This is confirmed by the partial abrogation of the inhibitory effects of anaemic sera on erythroid colony growth by anti-TNF-α neutralising antibodies . Furthermore, IL-6-induced hepcidin exerts a direct inhibitory effect on erythroblast proliferation and survival .

Another factor contributing to anemia of CHF patients is NO. Endothelial dysfunction associated with heart failure may alter endothelial NO synthase activity, hence further augmenting myocardial dysfunction due to increased oxidative stress . Paralleling these cardiodepressive actions, NO seems to have a direct inhibitory effect on bone marrow hematopoietic activity . Furthermore, it is of interest that NO inhibits blood cell formation in nonischemic murine CHF, whereas inflammatory cytokines, such as TNF-α, impair hematopoiesis in CHF following myocardial infraction .

A recent study suggests that vitamin D deficiency is independently associated with anemia in end-stage heart failure, based on the fact that vitamin D may stimulate erythropoiesis. On this study circulating 1,25-dihydroxyvitamin D was a better predictor of anemia than circulating 25-hydroxyvitamin D. Prospective randomized studies with administration of vitamin D will have to clarify if the association of vitamin D deficiency with anemia is causal .

In conclusion anemia in CHF is multifactorial. Two major factors contributing and exacerbating to its appearance are kidney dysfunction and iron deficiency. In 2003 this abnormality was described as cardio renal anemia syndrome (CRAS) , whereas the correction of anemia could play a major role in this vicious circle in improving the severity of CHF. In the last years, the role of iron has been recognized, as a major component of many energy-producing systems. In view of a possible independent association of iron deficiency and cardiac failure, renal failure and anemia, the same authors rename the syndrome as cardiorenal anemia iron deficiency (CRAID) syndrome .

4. Treatment of Anemia in Heart Failure

CHF is not just a hemodynamic disorder. It is the final common pathway of other conditions, where renal failure and anemia contribute to the progression to a more severe disease status. They also could be potential targets for intervention. Since the two major components of CHF anemia are iron deficiency and reduced EPO activity (absolute or functional in both cases), the main goals of intervention would be to increase their levels. Anemia treatment strategies in heart failure patients include erythropoiesis-stimulating agents (ESAs) and red blood cell transfusions. Iron replacement in iron-deficient patients with or without anemia has also been investigated. Before starting any treatment for anemia in CHF, it is necessary to exclude and treat, if possible, any other causes of anemia, such as active bleeding, hemolysis, vitamin B12 or folate deficiency, or even more chronic situations such as myelodysplastic syndromes and other malignancies.

Health Services Research & Development Service’s Evidence-based Synthesis Program has collected the literature from 1949 until November 2010 and published a review regarding the treatment of anemia in CHF and coronary heart disease patients . Despite the association with poorer outcomes, it remains unclear whether treating anemia or iron deficiency may improve outcomes.

It has been suggested that a small reduction of Hb levels may worsen the outcomes and symptoms of CHF, whereas the correction of anemia may improve NYHA classification, LVEF, LVH, and diuretic response . Treatment has been centered on administration of erythropoiesis-stimulating agents (ESAs) and parenteral iron supplementation, but most studies are poorly powered and therefore with limited validity. On the other hand, the only way to cause a rapid increase of Ht and therefore tissue oxygenation is the blood transfusion. Nevertheless, the only recommendations referring to anemia of CHF suggest treating any correctable causes of anemia, if this is evitable, such as iron, folate, or vitamin B12 deficiencies . The goal of Hb correction is also not well defined. Transfusion of packed red cells in Hb values lower than 9 g/dL or Ht less than 30% may be suggested, but in the setting of acute coronary syndromes this has been associated with higher mortality .

There are many data supporting that iron deficiency may contribute to the increased mortality in CHF patients. It has also been shown that correction of iron deficiency could improve symptoms and status of the syndrome. Nevertheless, this has not been adequately confirmed . There are several studies in CHF, with iron deficiency, with and without anemia, suggesting that correction of iron deficiency, using IV preparations, could improve symptoms and signs of CHF, such as S′-wave, E/E′ ratio, peak systolic strain rate, NYHA class, 6-minute walk distance, even without improvement of EF or rise of Hb levels, without major side effects . It is suggested, with high evidence, that correction of iron deficiency can improve exercise tolerance and duration, as well as the quality of life, in patients with stable CHF and mild CKD . There are also other studies suggesting that anemia in CHF can be corrected only with IV iron and not the oral forms , whereas long-term oral iron does not seem to improve any CHF parameters . This seems reasonable since in CHF there is increased hepcidin expression that blocks iron use, even if it is absorbed. In general terms it is preferred to administrate IV instead of oral iron, even though it can cause oxidative stress. When using intravenous preparations, the majority of the dose is deposited in long-term storage. There is a small portion of this iron that is rapidly bound to transferrin and available for transport to the bone marrow, bypassing the restrictions on iron release imposed by hepcidin. The use of large amounts of iron, delivered over minutes or hours as pulse therapy, could lead to poor utilization of this iron with tissue deposition, free radical formation, and increased risk of infection, because of a decrease in cellular immunity and promotion of bacterial growth . Other concerns of iron administration have to do with an increased risk of coronary heart disease, but still have not been confirmed . In conclusion, there are not efficient data proving evidence that iron administration in non-iron-deficient patients with CHF could improve the cardiac disease. It is however of great value to recognize iron deficiency, even in the absence of anemia and to correct it.

Regarding ESAs, there are only pilot studies for their use in the treatment of anemia of CHF. Uncontrolled hypertension and iron deficiency are contraindications. They are commonly used with simultaneous administration of IV iron, giving promising results in ameliorating symptoms and improving cardiac function, but only with very limited evidence . Moreover, the EPO receptor is present in many nonerythropoietic tissues, including myocardium, endothelium, vascular smooth muscle cells, and neurons, where EPO has shown tissue protective properties, because of its antiapoptotic action . Treatment with EPO in excitable murine and human left ventricular muscle preparations have resulted in an increase in twitch tension and in peak sarcomere shortening. This suggests that EPO exhibits direct positive inotropic and lusitropic effects in cardiomyocytes and ventricular muscle preparation, being mediated through PI3-K and PKCε isoform signalling, to directly affect both calcium release dynamics and myofilament function . Therefore, there could be an extra role of EPO in ameliorating symptoms, in addition to improving Hb levels. The major concern of EPO administration, based on hemodialysis experience, has to do with a possible increase of thrombotic risk, especially by overzealous correction of anemia or when iron-deficiency-associated thrombocytosis coexists. At present, there are not clearly defined targets of Hb in CKD anemia, although an Hb level of 10 g/dL seems to be a widely accepted goal.

Recently, there have been many studies of anemia in CHF patients with an effort to improve Hb levels. There have been used ESA and oral or IV iron and even IV iron without ESA, that have shown a positive effect on hospitalization, NYHA functional class, cardiac and renal function, quality of life, exercise capacity, and reduced BNP, without any increase in cardiovascular damage related to the therapy. However, adequately powered long-term placebo-controlled studies of ESA and IV iron in CHF are still needed and are currently being carried out . Nevertheless, until recently, there is high evidence that the use of ESA in stable CHF patients with serious renal disease did not have any particular effect on cardiovascular events, whereas there is moderate evidence that their use might have a negative impact on the survival .

Recent studies have recognized that dilutional anemia is highly prevalent in CHF patients. In this regard, arginine vasopressin antagonists might be an attractive treatment option, by increasing aquaresis. Until now, there is only indirect evidence supporting a rationale for their use. Therefore, future clinical research should explore the role of arginine vasopressin pathway activation in determining dilutional anemia and, ultimately, assess it as a therapeutic target .

Anemia is common in patients with heart disease. The evidence base to date does not convincingly support a role for ESAs for anemia correction. On the other hand, iron treatment may help ameliorate symptoms over the short term in patients with symptomatic heart failure. The role of blood transfusions remains understudied and unclear .

5. Conclusions

It seems that anemia exacerbates CHF, causing a vicious circle, where renal dysfunction and neurohormonal and proinflammatory cytokine activation participate in the development of anemia. On the other hand, anemia increases myocardial workload and worsens cardiac dysfunction. So, it is important to recognize any possible causes of anemia. It would also be beneficial to treat them, if possible. Administration of iron and ESAs seems to be promising, since they can both also improve factors other than anemia, but still there are many questions to be answered. These mainly concern their safety, the goals in Hb elevation, and probably their cost. Further studies are required to understand the association of anemia with CHF outcomes, to recognize the impact of anemia improvement, to asses when to initiate and when to cease the treatment, and finally to estimate the safety of these interventions.

Abbreviations

ACE: Angiotensin-converting enzyme
AcSDKP: N-acetyl-seryl-aspartyl-lysyl-proline
BNP: Brain natriuretic peptide
CHF: Congestive heart failure
CKD: Chronic kidney disease
CRAID: Cardio-renal-anemia-iron deficiency
CRAS: Cardio-renal anemia syndrome
eGFR: Estimated glomerula filtration rate
EF: Ejection fraction
EPO: Erythropoietin
ESAs: Erythropoiesis stimulating agents
Hb: Hemoglobin
IL-1,6,18: Interleukin-1,6,18
IV: Intravenous
LV: Left ventricular
NO: Nitric oxide
NYHA: New York heart association
TNF-α: Tumor necrosis factor-α.

Conflict of Interests

The authors declare no conflict of interests in their submitted paper.

By Stephen T. Sinatra, M.D., F.A.C.C., F.A.C.N., C.N.S., C.B.T.

It’s truly amazing how conditions that seemingly have nothing to do with the heart actually do impact heart health. It shows just how interconnected every single body part and system really is.

Anemia is a perfect example. Anemia is a condition that occurs when you don’t have enough red blood cells, or when your red blood cells don’t contain enough hemoglobin—the iron-rich protein that gives blood its red color. Hemoglobin helps red blood cells carry oxygen from the lungs to the rest of your organs and tissues.

Anemia Symptoms

Wondering if you’re anemic? Symptoms can vary. The most common is weakness, fatigue, and/or tiredness. Other symptoms of anemia may include shortness of breath, dizziness, headache, rapid heartbeat, irritability, and mental confusion.

One of the most interesting and unusual anemia symptoms is called pica. This is the habit of craving and eating unusual substances that have no nutritional value, such as ice, dirt, clay, even paper or cardboard! I’ll never forget a woman I went to medical school with who was a chronic ice chewer. I mean, she was seriously addicted to ice! We later found out she was anemic.

What Causes Anemic Symptoms?

Anemia strikes for a variety of reasons. The most common cause is iron deficiency. When the body lacks the iron needed to produce hemoglobin, anemia symptoms often kick in promptly. This usually occurs when you don’t get enough iron in the diet or, much more commonly, with blood loss. Women who have heavy menstrual periods run the risk of iron deficiency, as well as anyone who suffers from ulcers, gastritis, colon polyps, intestinal diseases, or any other condition that triggers bleeding. Anemia is also common in pregnancy, as a woman’s body needs to make additional blood to support a growing fetus.

Another form of anemia, megaloblastic anemia, results from folate or vitamin B12 deficiencies. Inadequate levels of these vitamins cause atypically large red blood cells that have a shorter-than-normal lifespan.

Other anemia causes include medical treatments such as chemotherapy and radiation, as well as the use of certain pharmaceuticals like antibiotics, seizure medications, immunosuppressants, and anticlotting drugs.

Anemia of Chronic Disease

The anemia cause that concerns me most as a cardiologist is what’s called “anemia of chronic disease.” With this form of anemia, the body does not efficiently recycle iron from blood cells, so they do not live as long as they should. The body also stops responding properly to erythropoietin, a hormone produced by the kidneys that’s responsible for boosting red blood cell production.

People with certain long-term medical conditions that involve inflammation, including some cancers and autoimmune disorders, hepatitis, kidney disease, and congestive heart failure (CHF) often become anemic. In fact, a meta-analysis of 34 studies and more than 153,000 CHF patients found that 37.2 percent of them had anemia. After a six-month follow-up, 46.8 percent of the anemic patients died compared with 29.5 percent without anemia.

Anemia also causes reduced blood flow to the kidneys, which leads to fluid retention, which places even further stress on the heart. Additionally, chronic anemia can result in left ventricular hypertrophy, the enlargement and thickening of the walls of the left ventricle—the heart’s main pumping chamber. This can worsen congestive heart failure and set up what researchers call a vicious cycle “wherein CHF causes anemia, and the anemia causes more CHF, and both damage the kidneys, worsening the anemia and the CHF further.”

So, yeah, I get concerned about anemia in patients with heart failure…and heart attack and other heart diseases. Decreased oxygen delivery leads to increased cardiac output. Simply put, this means the heart has to work much, much harder to do its job. Not only do nearly half of patients hospitalized for heart attack have anemia, people with anemia have a much higher risk of having a heart attack.

How to Treat Anemia

If you’re suffering from symptoms of anemia, see your doctor. He/she can run the appropriate tests, check for underlying health problems, and prescribe the right course of treatment.

Protect Yourself With These Heart Health Tests

What should you expect? In most cases, anemia treatment involves supplementing with iron (and/or folate or B12, if needed). If the underlying cause of anemia is blood loss (other than menstruation), then the source of the bleeding should also be located and stopped. Usually, that’s all it takes to solve the problem.

With anemia of chronic disease, though, more extensive treatment may be needed. Some research has shown that, in severe cases, blood transfusions, intravenous delivery of iron, and injections of erythropoietin can be very helpful.

One caveat…It’s important to keep in mind that iron can be a pro-oxidant, meaning it can lead to greater oxidative stress in the body if not used correctly. For this reason, the only people who should supplement with iron as a matter of course are menstruating and pregnant women. Iron supplementation is usually safe for children, but discuss dosing with your child’s pediatrician beforehand. Men, postmenopausal women, and all others should only take iron under the care and supervision of their doctors.

  • Khan Y and Tisman G. Pica in iron deficiency: a case series. J Med Case Reports. 2010;4:86.
  • Groenveld HF, Januzzi JL, et al. Anemia and mortality in heart failure patients: a systematic review and meta-analysis. J Am Coll Cardiol. 2008 Sep 2;52(10):818-27.
  • Silverberg DS, Wexler D, Iaina A. The role of anemia in the progression of congestive heart failure. Is there a place for erythropoietin and intravenous iron? J Nephrol. 2004 Nov-Dec;17(6):749-61.

Lack of iron regulating protein contributes to high blood pressure of the lungs

News Release

Wednesday, February 13, 2013

NIH mouse study also shows how gene regulates iron to control blood cell production.

Iron regulatory protein 1 (Irp1) detects iron levels in cells and directs either the storage or use of iron, depending on other conditions in the body. The researchers found that mice lacking Irp1 produced high levels of hypoxia inducible factor 2-alpha (HIF2 alpha), a protein produced in response to low oxygen conditions, like those that occur at high altitudes.

A protein known to regulate iron levels in the body has an unexpectedly important role in preventing a form of high blood pressure that affects the lungs, and in stabilizing the concentration of red cells in blood, according to a study in mice by researchers at the National Institutes of Health.

In mice, lack of iron regulatory protein 1 (Irp1) results in pulmonary hypertension, a form of high blood pressure that affects the lungs, and to polycythemia, a rare disorder in which the body produces excess red blood cells.

“This insight might lead to progress in treating cases of polycythemia or pulmonary hypertension without a known cause,” said senior author Tracey A. Rouault, M.D., of the Division of Intramural Research (DIR) at the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), where the research was conducted. It’s possible, she added, that human cases of these disorders might result from malfunctioning copies of the gene for Irp1.

The study also provides insight into how the body directs iron into the manufacture of blood to prevent anemia, the deficiency of red blood cells.

The findings appear in Cell Metabolism.

Dr. Rouault collaborated with more than a dozen other NIH researchers, including first authors Manik C. Ghosh, Ph.D., and Deliang Zhang, Ph.D., also of the NICHD’s DIR, as well as researchers at the NIH Veterinary Resources Program and the National Heart, Lung and Blood Institute. Researchers from the University of Colorado School of Medicine, Denver, and thoxia inducible factor 2-alpha (HIF2 alpha), a protein produced in response to le University of Nebraska–Lincoln were also part of the team.

Iron regulatory protein 1 (Irp1) detects iron levels in cells and directs either the storage or use of iron, depending on other conditions in the body. The researchers found that mice lacking Irp1 produced high levels of hypow oxygen conditions, like those that occur at high altitudes. In turn, HIF2 alpha spurs production of the hormone erythropoietin, which stimulates the production of red blood cells.

When the animals were put on low-iron diets, they did not become anemic, but instead developed polycythemia and pulmonary hypertension.

In people, polycythemia and high blood pressure in the lungs are rare conditions, and in some cases occur without a known cause. It is possible that changes in the gene for Irp1 may account for some of these cases, the researchers suggest.

To investigate Irp1’s role in regulating the body’s use of iron, the researchers reared mice lacking the gene that makes Irp1 and divided the animals into two groups, feeding one group a normal diet and the other a low iron diet.

Within a year, less than 40 percent of the mice on the low-iron diet had survived. Most had died from abdominal hemorrhaging. The researchers found that the mice on low iron diets had high levels of HIF2 alpha in the lungs and kidney. These animals produced high levels of erythropoietin, which resulted in polycythemia. HIF2 alpha also triggered increased production of a substance known as endothelin-1 in the lungs, which likely contributed to the development of pulmonary hypertension.

“Irp1 appears to be the switch that controls whether HIF2 alpha protein is made,” Dr. Zhang said.

This research also provided insight into how Irp1 functions under normal circumstances Dr. Rouault explained. The researchers theorize that in low-iron conditions, Irp1 allows the production of HIF2 alpha. HIF2 alpha then triggers production of erythropoietin, to generate more red blood cells. To supply iron for the red blood cells, iron is removed from the tissues. When tissue iron levels decline too much, Irp1 halts production of HIF2 alpha, and production of new blood cells ceases, conserving the body’s remaining iron stores. Production of red blood cells then declines, leading to anemia.

About the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD): The NICHD sponsors research on development, before and after birth; maternal, child, and family health; reproductive biology and population issues; and medical rehabilitation. For more information, visit the Institute’s website at http://www.nichd.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit www.nih.gov.

NIH…Turning Discovery Into Health®

The Facts About Iron-Deficiency Anemia and Your Heart

If you have a health condition that affects your heart — such as high blood pressure, diabetes, coronary artery disease, or heart failure — then it’s important to be aware of another condition that can affect your heart health: iron deficiency anemia.

Iron deficiency anemia develops when the body doesn’t have enough iron to adequately produce red blood cells, which are responsible for transporting oxygen throughout the body. While it’s especially common in developing countries and among women of reproductive age, recent evidence suggests that iron deficiency anemia is also more common than previously believed in adults with heart conditions.

While iron deficiency anemia can make heart conditions worse — or even cause them, if it’s severe enough — any damage can usually be reversed if the anemia is detected and treated early enough. Here’s what you should know about iron deficiency anemia and its impact on heart health.

A Range of Symptoms

The symptoms of iron deficiency anemia are caused by inadequate oxygen in the body’s tissues, says Daniel A. Landau, MD, a hematologist and oncologist at Orlando Health UF Health Cancer Center in Orlando, Florida. “It’s an issue of supply and demand,” he says, adding that fatigue is the most common symptom, reported by about 90 percent of people that he sees with the condition.

Other common symptoms, Dr. Landau says, include dizziness or fainting and lack of mental sharpness. In some cases, people experience the urge to eat abnormal things like dirt or chalk — a condition known as pica.

But Landau emphasizes that iron deficiency isn’t usually an isolated condition. “We don’t normally become iron deficient just because we’re not eating the right diet,” he says. “Normally, it’s because of blood loss or some other issue” that may require urgent treatment — such as gastrointestinal bleeding or even colon cancer.

According to Ezra A. Amsterdam, MD, a cardiologist and professor of medicine at the University of California, Davis, Medical Center in Sacramento, a poor diet alone is “certainly responsible for milder forms of iron deficiency anemia” in many people.

And in mild to moderate anemia, Dr. Amsterdam notes, symptoms like fatigue may not be very pronounced. “People can do relatively well in limited activities, though not strenuous ones,” he says. In that case, “an adult who is not leading a life of major exertion can do what needs to be done.”

Because of the potential for a lack of overt symptoms, Amsterdam emphasizes the importance of having an annual exam with your doctor. “A lot of these symptoms are nonspecific,” he adds, so they could point to some other condition and therefore should be checked out.

The Link to Heart Health

“I think the link between iron deficiency and heart health was very poorly understood until recently,” says Landau — but studies in recent years have shed some light on this relationship.

As noted in an article published in March 2013 in the European Heart Journal, one study that used a bone marrow biopsy — considered the “gold standard” for detecting iron deficiency — found that 73 percent of people with both heart failure and anemia had iron deficiency, indicating that it may play a key role in heart disease.

And a study published in July 2017 in the journal Acta Cardiologica found that among people with heart failure, iron deficiency is associated with worse exercise performance, along with a higher rate of hospitalization and death from all causes if it’s allowed to progress.

Amsterdam explains that in cases of severe anemia, the heart tends to compensate for the lack of red blood cells reaching the body’s tissues by pumping faster, a condition known as tachycardia. Over time, he says, this can lead to enlargement of the heart and, ultimately, heart failure, in which the heart can no longer pump enough blood to meet the body’s needs. Symptoms of heart failure can include fluid retention, shortness of breath, weakness, and very low blood pressure.

Heart failure caused directly by severe anemia is relatively rare, according to Amsterdam. “In my experience,” he says, “it’s not something that we see on a daily or even weekly basis.”

But if you have heart disease already, Amsterdam notes that even less severe cases of iron deficiency anemia can contribute to noticeable heart-related symptoms like shortness of breath or angina (chest pain). “It’s a continuum,” he says. “It all depends on the individual patient’s adaptability to these stresses,” which will be curtailed if you already have a condition like high blood pressure or coronary artery disease.

Screening and Treatment

If you’re experiencing any of the symptoms associated with iron deficiency anemia, it’s crucial to see your doctor to find out what’s going on. “The first screening test is just to figure out whether you are anemic or not,” says Landau. If you are anemic, your doctor will try to establish whether it’s due to iron deficiency or some other cause, like a vitamin deficiency, underlying chronic inflammation, kidney disease, or poor thyroid function. Possible loss of blood from your gastrointestinal tract may also be investigated.

If you’re found to be iron deficient, Landau says, your doctor will most likely start you on an oral supplement, which may be iron tablets or simply a multivitamin containing iron, depending on the amount you need.

If you’re found to have a severe iron deficiency, Amsterdam notes, you’ll most likely be given an intravenous (IV) iron infusion right away. If someone is severely anemic, he says, the results of an iron infusion can sometimes be “like magic” in terms of restoring energy and resolving symptoms.

Most of the time, though, Amsterdam says, an infusion or two will need to be followed up by oral iron supplements, which will result in slow and steady progress rather than an instant improvement.

According to an article published in August 2017 in the journal Cardiovascular Therapeutics, among people with heart failure and iron deficiency, IV iron infusions were shown to improve symptoms, exercise capacity, and overall quality of life, both immediately and over time.

Landau notes that if a person doesn’t tolerate oral iron supplements well and experiences nausea, constipation, or diarrhea, that person may also be a candidate for IV iron, even if he or she is not severely anemic. “Intravenous iron works fantastically,” he says, “if the patient can’t tolerate oral iron for any reason.”

While an iron-rich diet may help you maintain healthy iron levels, if you’re already anemic, Landau says that dietary changes alone are unlikely to do you much good. “Diet, by itself,” he says, “is an inefficient way to fix the iron issue.”

But proper treatment of iron deficiency, according to Landau, can make a big difference for people with heart conditions. “If you fix the iron deficiency,” he says, “they usually feel better.”

Symptoms and Signs of Anemia

Anemia Causes

Many medical conditions cause anemia. Common causes of anemia include the following:

  • Anemia from active bleeding: Loss of blood through heavy menstrual bleeding or wounds can cause anemia. Gastrointestinal ulcers or cancers such as cancer of the colon may slowly ooze blood and can also cause anemia.
  • Iron deficiency anemia: The bone marrow needs iron to make red blood cells. Iron (Fe) plays an important role in the proper structure of the hemoglobin molecule. If iron intake is limited or inadequate due to poor dietary intake, anemia may occur as a result. This is called iron deficiency anemia. Iron deficiency anemia can also occur when there are stomach ulcers or other sources of slow, chronic bleeding (colon cancer, uterine cancer, intestinal polyps, hemorrhoids, etc). In these kinds of scenarios, because of ongoing, chronic slow blood loss, iron is also lost from the body (as a part of blood) at a higher rate than normal and can result in iron deficiency anemia.
  • Anemia of chronic disease: Any long-term medical condition can lead to anemia. The exact mechanism of this process in unknown, but any long-standing and ongoing medical condition such as a chronic infection or a cancer may cause this type of anemia.
  • Anemia related to kidney disease: The kidneys release a hormone called the erythropoietin that helps the bone marrow make red blood cells. In people with chronic (long-standing) kidney disease (CKD or end stage renal disease (ESRD), the production of this hormone is diminished, and this, in turn, diminishes the production of red blood cells, causing anemia. This is called anemia related to or anemia of chronic kidney disease.
  • Anemia related to pregnancy: Water weight and fluid gain during pregnancy dilutes the blood, which may be reflected as anemia since the relative concentration of red blood cells is lower.
  • Anemia related to poor nutrition: Vitamins and minerals are required to make red blood cells. In addition to iron, vitamin B12 and folate (or folic acid) are required for the proper production of hemoglobin (Hgb). Deficiency in any of these may cause anemia because of inadequate production of red blood cells. Poor dietary intake is an important cause of low folate and low vitamin B12 levels. Strict vegetarians who do not take sufficient vitamins are at risk to develop vitamin B12 deficiency.
  • Pernicious anemia: There also may be a problem in the stomach or the intestines leading to poor absorption of vitamin B12. This may lead to anemia because of vitamin B12 deficiency known as pernicious anemia.
  • Sickle cell anemia: In some individuals, the problem may be related to production of abnormal hemoglobin molecules. In this condition, the hemoglobin problem is qualitative, or functional. Abnormal hemoglobin molecules may cause problems in the integrity of the red blood cell structure and they may become crescent-shaped (sickle cells). There are different types of sickle cell anemia with different severity levels. This is typically hereditary and is more common in those of African, Middle Eastern, and Mediterranean ancestry. People with sickle cell anemia can be diagnosed as early as childhood depending on the severity and symptoms of their disease.
  • Thalassemia: This is another group of hemoglobin-related causes of anemia. There are many types of thalassemia, which vary in severity from mild (thalassemia minor) to severe (thalassemia major). These are also hereditary, but they cause quantitative hemoglobin abnormalities, meaning an insufficient amount of the correct hemoglobin molecules is made. Thalassemia is more common in people from African, Mediterranean, and Southeast Asian ancestries.
  • Alcoholism: Poor nutrition and deficiencies of vitamins and minerals are associated with alcoholism. Alcohol itself may also be toxic to the bone marrow and may slow down the red blood cell production. The combination of these factors may lead to anemia in alcoholics.
  • Bone marrow-related anemia: Anemia may be related to diseases involving the bone marrow. Some blood cancers such as leukemia or lymphomas can alter the production of red blood cells and result in anemia. Other processes may be related to a cancer from another organ spreading to the bone marrow.
  • Aplastic anemia: Occasionally some viral infections may severely affect the bone marrow and significantly diminish production of all blood cells. Chemotherapy (cancer medications) and some other medications may pose the same problems.
  • Hemolytic anemia: The normal red blood cell shape is important for its function. Hemolytic anemia is a type of anemia in which the red blood cells rupture (known as hemolysis) and become dysfunctional. This could happen due to a variety of reasons. Some forms of hemolytic anemia can be hereditary with constant destruction and rapid reproduction of red blood cells (for example, as in hereditary spherocytosis, hereditary elliptocytosis, and glucose-6-phosphate dehydrogenase or G6GD deficiency). This type of destruction may also happen to normal red blood cells in certain conditions, for example, with abnormal heart valves damaging the blood cells or certain medications that disrupt the red blood cell structure.
  • Anemia related to medications: Many common medications can occasionally cause anemia as a side effect in some individuals. The mechanisms by which medications can cause anemia are numerous (hemolysis, bone marrow toxicity) and are specific to the medication. Medications that most frequently cause anemia are chemotherapy drugs used to treat cancers (chemotherapy-induced anemia). Other common medications that can cause anemia include some seizure medications, transplant medications, HIV medications, some malaria medications, some antibiotics (penicillin, chloramphenicol), antifungal medications, and antihistamines.
  • Other less common causes of anemia include thyroid problems, cancers, liver disease, autoimmune diseases (lupus), paroxysmal nocturnal hemoglobinuria (PNH), lead poisoning, AIDS, malaria, viral hepatitis, mononucleosis, parasitic infections (hookworm), bleeding disorders, and insecticide exposure. It is noteworthy that there are many other potential causes of anemia that are not included in this list as these are only some of the more common and important ones.

Iron-Deficiency Anemia

What is iron-deficiency anemia?

The most common cause of anemia worldwide is iron deficiency. Iron is needed to form hemoglobin, part of red blood cells that carry oxygen and remove carbon dioxide (a waste product) from the body. Iron is mostly stored in the body in the hemoglobin. About one-third of iron is also stored as ferritin and hemosiderin in the bone marrow, spleen, and liver.

What causes iron-deficiency anemia?

Iron-deficiency anemia may be caused by the following:

  • Diets low in iron. Iron is obtained from foods in our diet; however, only 1 mg of iron is absorbed for every 10 to 20 mg of iron ingested. A person unable to have a balanced iron-rich diet may suffer from some degree of iron-deficiency anemia.

  • Body changes. An increased iron requirement and increased red blood cell production is required when the body is going through changes, such as growth spurts in children and adolescents, or during pregnancy and lactation.

  • Gastrointestinal tract abnormalities. Malabsorption of iron is common after some forms of gastrointestinal surgeries. Most of the iron taken in by foods is absorbed in the upper small intestine. Any abnormalities in the gastrointestinal (GI) tract could alter iron absorption and result in iron-deficiency anemia. Surgery or medications that stop stomach acid production will also decrease iron absorption.

  • Blood loss. Loss of blood can cause a decrease of iron and result in iron-deficiency anemia. Sources of blood loss may include GI bleeding, menstrual bleeding, or injury.

What are the symptoms of iron-deficiency anemia?

The following are the most common symptoms of iron-deficiency anemia. However, each individual may experience symptoms differently. Symptoms may include:

  • Abnormal paleness or lack of color of the skin

  • Irritability

  • Lack of energy or tiring easily (fatigue)

  • Increased heart rate (tachycardia)

  • Sore or swollen tongue

  • Enlarged spleen

  • A desire to eat peculiar substances such as dirt or ice (a condition called pica)

The symptoms of iron-deficiency anemia may resemble other blood conditions or medical problems. Always consult your doctor for a diagnosis.

How is iron-deficiency anemia diagnosed?

Iron-deficiency anemia may be suspected from general findings on a complete medical history and physical examination, such as complaints of tiring easily, abnormal paleness or lack of color of the skin, or a fast heartbeat (tachycardia). Iron-deficiency anemia is usually discovered during a medical examination through a blood test that measures the amount of hemoglobin (number of red blood cells) present, and the amount of iron in the blood. In addition to a complete medical history and physical examination, diagnostic procedures for iron-deficiency anemia may include the following:

  • Additional blood tests for iron

  • Bone marrow aspiration and/or biopsy. A procedure that involves taking a small amount of bone marrow fluid (aspiration) and/or solid bone marrow tissue (called a core biopsy), usually from the hip bones, to be examined for the number, size, and maturity of blood cells and/or abnormal cells. This test is usually not necessary.

  • Upper and/or lower endoscopy. These tests may help rule out a source of blood loss.

Treatment for iron-deficiency anemia

Specific treatment for iron-deficiency anemia will be determined by your doctor based on:

  • Your age, overall health, and medical history

  • Extent of the anemia

  • Cause of the anemia

  • Your tolerance for specific medications, procedures, or therapies

  • Expectations for the course of the anemia

  • Your opinion or preference

Treatment may include:

  • Iron-rich diet. Eating a diet with iron-rich foods can help treat iron-deficiency anemia. Good sources of iron include the following:

    • Meats, such as beef, pork, lamb, liver, and other organ meats

    • Poultry, such as chicken, duck, turkey, (especially dark meat), liver

    • Fish, such as shellfish, including clams, mussels, and oysters, sardines, anchovies

    • Leafy greens of the cabbage family, such as broccoli, kale, turnip greens, and collards

    • Legumes, such as lima beans and green peas; dry beans and peas, such as pinto beans, black-eyed peas, and canned baked beans

    • Yeast-leavened whole-wheat bread and rolls

    • Iron-enriched white bread, pasta, rice, and cereals

  • Iron supplements. Iron supplements can be taken over several months to increase iron levels in the blood. Iron supplements can cause irritation of the stomach and discoloration of bowel movements. They should be taken on an empty stomach, or with orange juice, to increase absorption. They are much more effective than dietary interventions alone. In cases of malabsorption or intolerance, IV iron may be needed.

  • Evaluation for a source of blood loss. This may include upper endoscopy or colonoscopy.

How does the body process iron?

Iron is present in many foods and absorbed into the body through the stomach. During this process of absorption, oxygen combines with iron and is transported into the plasma portion of blood by binding to transferrin. From there, iron and transferrin are used in the production of hemoglobin, stored in the liver, spleen, and bone marrow, and utilized as needed by all body cells.

The following is a list of foods that are good sources of iron. Always consult your doctor regarding the recommended daily iron requirements for your particular situation.

Iron-Rich Foods

Quantity

Approximate Iron
Content
(milligrams)

Oysters

3 ounces

Beef liver

3 ounces

Prune juice

1/2 cup

Clams

2 ounces

Walnuts

1/2 cup

Ground beef

3 ounces

Chickpeas

1/2 cup

Bran flakes

1/2 cup

Pork roast

3 ounces

Cashew nuts

1/2 cup

Shrimp

3 ounces

Raisins

1/2 cup

Sardines

3 ounces

Spinach

1/2 cup

Lima beans

1/2 cup

Kidney beans

1/2 cup

Turkey, dark meat

3 ounces

Prunes

1/2 cup

Roast beef

3 ounces

Green peas

1/2 cup

Peanuts

1/2 cup

Potato

Sweet potato

1/2 cup

Green beans

1/2 cup

Egg

I. Anemia: What every physician needs to know.

The presence of anemia in heart failure (HF) patients is associated with cognitive impairment, a higher New York Heart Association (NYHA) class, lower exercise capacity, worse quality of life, increased number of hospitalizations, and higher mortality.

Although the prevalence and prognostic roles of anemia have been well defined, its pathophysiology continues to be investigated. An intense search has been under way to determine whether anemia in HF is a marker or a mediator of adverse prognosis.

II. Diagnostic Confirmation: Are you sure your patient has Anemia?

Anemia is defined by the World Health Organization (WHO) as hemoglobin concentration <13.0 g/dl in men and <12.0 g/dl in premenopausal woman. This definition, however, has several limitations and was not intended to serve as the gold standard to define anemia.

Other definitions include the National Kidney Foundation criteria of hemoglobin <12.0 g/dl in men and <11.0 g/dl in premenopausal women and the newly derived definitions based on large samples from the third U.S. National Health and Nutrition Examination Survey and the Scripps-Kaiser database of hemoglobin with <13.7 and <12.9 g/dl in white and black men, respectively, and <12.2 and <11.5 g/dl in white and black women, respectively.

It is important to note the following regarding definitions of anemia.

  • The lower values in women compared with men are remarkably consistent across the various definitions.

  • The lower values in African Americans are not widely recognized.

  • Volume status may influence the diagnosis of anemia. Hemoglobin and hematocrit values are reduced in the presence of increased plasma volume and they inversely increase with diuresis.

  • No HF specific criteria for anemia have been developed. (Similar to the revised WHO/National Cancer Institute criteria for men and women with malignancy <14.5 g/dl and 12 g/dl, respectively)

A. History Part I: Pattern Recognition:

Anemia is more common in women, the elderly, African Americans, and in patients with diabetes, chronic kidney disease, and those with a lower body mass index. It is also more common in HF patients with a higher NYHA classification and higher left ventricular ejection fraction (Table 1).

Table 1.n

Characteristics of Heart Failure Patients with Anemia

The symptoms of anemia closely mimic those of HF, including dyspnea, fatigue, weakness, cognitive impairment, and poor exercise capacity, and the superimposition of anemia in patients with HF may exacerbate these symptoms (Table 2).

Table 2.n

Anemia in Heart Failure

Therefore, the development of anemia may lead to an earlier recognition of the presence of HF.

In patients with ischemic HF, precipitation or potentiation of ischemia may occur when the anemia is severe.

B. History Part 2: Prevalence:

The prevalence of anemia in HF varies (9% to 70%) according to the definition used, and patient population (inpatient vs outpatient, preserved vs impaired left ventricular systolic function, young vs old, men vs women). The overall prevalence in community patients with heart failure approaches 50%.

The prevalence of anemia in HF appears to be increasing as is evident in a study in Olmsted County in two periods (1979-2002, 40%), and (2003-2006, 53%). The reason for the increasing prevalence of anemia has been attributed to the increasing prevalence of diastolic HF.

C. History Part 3: Competing diagnoses that can mimic Anemia.

Several symptoms are shared by HF and anemia, and therefore establishing the presence or absence of anemia in patients with HF by laboratory testing is mandatory.

It should be noted that if anemia is severe, it may cause high output HF.

D. Physical Examination Findings.

In severe anemia, tachycardia and bounding pulses are present, there is pallor of the skin and mucous membranes, and a pulmonary midsystolic murmur is commonly present.

E. What diagnostic tests should be performed?

  • Complete blood count (CBC) is obtained routinely and includes hemoglobin, hematocrit, red blood cell indices including red cell distribution width, and reticulocyte count.

  • A standard procedure in the workup of any anemia is the examination of the peripheral blood smear.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

The potential presence of multiple causes of anemia in HF dictates the assessment of the iron profile, the measurement of vitamin B12 folic acid, and the assessment of thyroid function tests.

Ferritin values of 30 to 40 ng/ml are used to define iron deficiency in individuals who do not have inflammatory disease. In the presence of inflammation, however, ferritin levels are increased because it is an acute phase reactant.

The ratio of serum transferring receptors (reflect tissue iron availability) to ferritin has been proposed to distinguish between anemia due to iron deficiency versus inflammation (anemia of chronic disease). A ratio of <1 favors the presence of inflammation, and >2 the presence of iron deficiency with or without inflammation.

2. Serum creatinine and estimated glomerular filtration rate

3. Serum levels of vitamin B12 and folic acid

4. Thyroid function tests

Functional iron deficiency is characterized by inability to use available iron stores. A criterion of a ferritin level of 100 to 300 mg/dl in combination with transferrin saturation <20% has been suggested to define this condition.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

To verify the presence of hemodilution, blood volume analysis with the 51-chromium labeling technique or with I131 – tagged albumin could be considered; its use, however, has been restricted to research.

III. Management.

The etiology of anemia needs to be identified for the proper management of anemia. The causes of anemia in HF include the following (Table 3): hemodilution, inflammation (Table 4), renal impairment, iron deficiency, medications (angiotensin-converting enzymes inhibitors , angiotensin receptor antagonists and carvedilol ), vitamin B12 and folic acid deficiency, and thyroid function abnormalities.

Table 3.n

Causes of Anemia in Heart Failure

Table 4.n

Anemia of Inflammation

Table 5.n

ACE Inhibitors and ARB

Table 6.n

Carvedilol

The only consensus in the management of anemia in HF is in correcting hematinic deficiencies that include iron, vitamin B12, and folic acid.

Iron deficiency is relatively common (at least one third) in patients with HF and may be caused by interference with iron absorption by hepcidin, poor dietary intake, an edematous gastrointestinal tract, or blood loss secondary to medications (acetylsalicylic acid and warfarin). Iron deficiency should be identified and is usually treated with oral supplementation (Table 7).

Table 7.n

Eythropoeitin release

Hemoglobin rises within 2 weeks, the deficit is half corrected at 4 weeks, and fully corrected at 8 weeks. On occasion, when a failure to respond to oral supplementation is noted, iron could be administered intravenously. Several preparations are available, such as ferric gluconate complex, iron sucrose, and ferric carboxymaltose (Table 8).

Table 8.n

Oral Supplements

Despite the symptomatic improvement reported with intravenous iron in patients with HF, its role as a therapeutic intervention may await further classification of its impact on morbidity and mortality and long-term safety.

The available evidence does not support the use of erythropoietin stimulating agents (ESA) in the correction of anemia in patients with anemia and HF, because the risk/benefit ratio is not known at present.

A. Immediate management.

The only indication for blood transfusion is the presence of severe anemia. No HF specific cut-off has been proposed and the general recommendation for initiation transfusion when hemoglobin is <7 gm/dl applies. Red cell preparation and not whole blood should be selected to minimize volume overload, and concomitant diuretics need to be administered in the vast majority of patients with HF to avoid volume overload.

C. Laboratory Tests to Monitor Response To, and Adjustments in, Management.

The use of iron supplementation for the correction of iron deficiency anemia could be monitored by repeating hemoglobin in 4 weeks (half way correction) and 8 weeks (Table 9). Restoring iron stores requires a minimum of 6 months of treatment. In the occasional patient who fails to respond to oral supplementation, an intravenous preparation could be considered.

Table 9.n

Iron Supplementation

D. Long-term management.

Erythropoietin is a pleiotropic cytokine of renal origin produced in response to hypoxia to promote survival of red blood cells by inhibiting apoptosis of erythroblasts. Increasing hemoglobin and thereby oxygen delivery could be achieved by the administration of erythropoiesis stimulating agents.

However, their use in non-HF patients has been associated with undesirable affects, including elevated blood pressure, thrombotic events including stroke and increased risk of death. Hemodynamically they cause an increase in peripheral vascular resistance, a reduction in cardiac output, and lowering of left ventricular ejection fraction.

The use of erythropoiesis stimulating agents for the treatment of anemia in HF will be determined by the findings of the Reduction of Events with Darbepoetin Alfa in Heart Failure (RED-HF) trial in which patients with systolic HF and anemia were randomized to darbepoetin alfa or a placebo.

E. Common Pitfalls and Side-Effects of Management

Oral iron supplementation may be associated with gastrointestinal side effects, including constipation or diarrhea, abdominal discomfort, or nausea and vomiting.

The side effects of intravenous iron are related to the specific preparation. In the Fair-HF trial, the adverse events in the group receiving ferric carboxymaltose were similar to the placebo group.

IV. Management with Co-Morbidities

There are no data that guide the management of anemia in patients with HF who have concomitant comorbidities including renal impairment and diabetes mellitus.

It would be useful, however, to review the available experience in the predominantly non-HF population.

Chronic kidney disease with anemia

Two studies have suggested that achievement of a higher hematocrit or hemoglobin target was associated with higher cardiovascular risk. In the United States Normal Hematocrit trial, hemodialysis patients (n = 1,233) with a baseline hematocrit of 27% to 33% were randomly assigned to receive epoetin to a target hematocrit of either 30% or 42%.

The study was terminated prematurely because of a trend toward higher mortality and myocardial infarction in the higher hematocrit group. In the Correction of Hemoglobin and Outcomes in Renal Insufficiency (CHOIR) study, patients (n = 1,432) with chronic renal failure (GFR 27.2 ml/min/1.77 m2) and anemia (hemoglobin 10.1 ± 0.9 g/dl) were randomly assigned to receive epoetin alfa to achieve a target hemoglobin of 13.5 g/dl or 11.3 g/dl.

The higher hemoglobin target group experienced an increased incidence of the composite endpoint (death, myocardial infarction, hospitalization for HF and stroke). Only 23% of the patients in CHOIR had a history of HF.

A third study, the Cardiovascular Risk Reduction by Early Anemia Treatment with Epoetin Beta (CREATE) in a similar patient population (n = 603), GFR 24.5 ml/min/1.73 m2, and hemoglobin 11.06, correction of hemoglobin to a target level of 13.0 to 15.0 g/dl compared with subnormal range (10.5 to 11.5 g/dl) was not associated with an increased incidence of cardiovascular events, (sudden death, myocardial infarction, acute HF, stroke, transient ischemic attack (TIA), hospitalization for angina or arrhythmia, and complication of peripheral vascular disease). Less than one third (32%) of the patients had a history of HF.

Based on these studies, the U.S. Food and Drug Administration (FDA) revised its recommendations for consideration of initiating ESAs to hemoglobin <10 g/dl and removed the previously recommended target range of 10 to 12 g/dl. Instead, it added a statement indicating an increasing risk of serious cardiovascular events when ESAs were dosed to a target hemoglobin >11 g/dl.

Chronic kidney disease, diabetes mellitus, and anemia

In the Trial to Reduce Cardiovascular Events With Aranesp Therapy (TREAT), in which 4,044 patients with type 2 diabetes mellitus, chronic kidney disease, and anemia (hemoglobin ≤ 11.0 g/dl) were randomized to a placebo or darbepoetin alfa with a target hemoglobin of 13.0 g/dl, an increased risk of stroke was associated with treatment with darbepoetin alfa. No excessive risk, however, was noted in patients (n = 1,345) with a history of HF.

A subsequent analysis from TREAT demonstrated that a poor initial response to darbepoetin alfa requiring escalating doses was associated with increased risk of death or cardiovascular events, which raised concerns about the appropriateness and safety of targeting higher hemoglobin level as well as the need to assess responsiveness to ESAs.

Therefore, the available data derived primarily from non-HF patients do not support targeting a higher level of hemoglobin with the use of ESAs.

A. Appropriate Prophylaxis and Other Measures to Prevent Readmission.

Until the role of anemia as a marker or a mediator of adverse events is clarified, a firm recommendation cannot be made. One relatively large randomized study documented improvement in NYHA functional class, self-reported patient global assessment, and health-related quality of life with intravenous iron; however, the impact on morbidity and long-term safety has not been assessed.

B. What’s the Evidence for specific management and treatment recommendations?

None of the current HF guidelines provide recommendations. The 2008 European Society of Cardiology guidelines state that correction of anemia has not been established as routine therapy.

Beutler, E, Waalen, J. “The definition of anemia: what is the lower limit of normal of the blood hemoglobin concentration?”. Blood. vol. 107. 2006. pp. 1747-50. (A must read review of the limitations of WHO definition of anemia and the proposed newer criteria stratified by sex and race/ethnicity and derived from two large databases.)

Jelkmann, W. “Erythropoietin after a century of research: younger than ever”. Eur J Haematol. vol. 78. 2007. pp. 183-205. (An excellent summary of erythropoietin biology, including its cardioprotective potential.)

Lindenfeld, J. “Prevalence of anemia and effects on mortality in patients with heart failure”. Am Heart J.. vol. 149. 2005. pp. 391-401. (An extensive review of the prevalence of anemia in HF in the inpatient and outpatient settings, as well as its association with mortality.)

Dunlay, DM, Weston, SA, Redfield, MM. “Anemia and heart failure: a community study”. Am J Med. vol. 121. 2008. pp. 726-32. (A study in two cohorts in the community demonstrating an increase overtime in the prevalence of anemia in HF with higher prevalence in patients with preserved left ventricular ejection fraction.)

Groenveld, HF, Januzzi, JL, Damman, K. “Anemia and mortality in heart failure patients: a systematic review and meta-analysis”. J Am Coll Cardiol. vol. 52. 2008. pp. 818-27. (A systematic review of literature involving 153,180 patients with HF demonstrating an independent association of anemia, with mortality in patients with both preserved and impaired left ventricular ejection fraction.)

Tang, WHW, Tong, W, Jain, A. “Evaluation and long-term prognosis of new onset, transient, and persistent anemia in ambulatory patients with chronic heart failure”. J Am Coll Cardiol. vol. 51. 2008. pp. 569-76. (This study shows the dynamic nature of anemia in HF and the relevance of persistent as well as the development of new anemia in long-term prognosis.)

Desai, A, Lews, E, Solomon, S, McMurry, JJV, Pfeffer, M. “Impact of erythropoiesis-stimulating agents on morbidity in patients with heart failure: an updated, post-TREAT meta-analysis”. Eur J Heart Fail. vol. 12. 2010. pp. 936-42. (A systemic review and meta-analysis of nine placebo controlled studies enrolling 2,039 patients with HF. The use of ESAs was associated with a neutral effect on mortality and HF hospitalization.)

C. DRG Codes and Expected Length of Stay.

Several studies have reported an association of anemia with increased length of stay in patients hospitalized with HF. It is not clear, however, whether anemia is a marker or a mediator.

Useful Definitions

Erythropoietin (EPO): A peptide hormone, made primarily in the kidney, which promotes the maturation of erythrocyte precursors into mature RBC by blocking apoptosis in the blast cell lineage.

Ferritin: The protein in the RES that serves to store extra body iron.

Transferrin: The major plasma transport protein that carries iron from its storage site in reticuloendothelial system (RES) to the bone marrow.

Transferrin receptor (TFR): A receptor on the surface of erythroblasts in the marrow, which internalizes the iron-transferrin complex to provide iron to the cell.

Ferroportin (Fp): A transmembrane protein on the surface of the RES cell that delivers storage iron to the plasma.

Hepcidin: A peptide in the plasma that internalizes Fp, thereby blocking release of storage iron from the RES and limiting absorption of dietary iron.

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