Though up to 70% of patients with CHF have anemia, current studies indicate that the specific cause of anemia in heart failure remains unclear. What we do know is that the cause is multifactorial. Iron deficiency, decreased EPO levels, chronic inflammation, and activation of RAAS are the causes most supported by the data.

Iron deficiency

The pathophysiology of iron deficiency in heart failure is not fully understood, and research is underway to study iron homeostasis, the role of iron-regulating hormones, and the effects of iron deficiency on cardiac function. Underlying causes for iron deficiency in HF are suggestive to be due to advanced age, malnutrition, chronic inflammation, renal failure, increased iron losses, and reduced iron absorption. 

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Decreased erythropoietin levels

Patients with heart failure also often have renal failure and anemia, a condition referred to as cardio renal anemia (CRA) syndrome. CHF is characterized by increased renal sympathetic nerve activity and chronic activation of RAAS, both of which contribute to decreased renal blood flow.

With reduced renal blood flow, the kidneys experience hypoxia and ischemia, which leads to renal insufficiency and decreased production of erythropoietin. 

Chronic inflammation

Though the exact pathophysiological process of anemia caused by inflammation is not known, it is thought to be related to increases in both pro-inflammatory cytokines and hepcidin, which is a hormone that regulates the body’s use of iron. To further potentiate anemia, elevated levels of some cytokines inhibit erythropoietin production and suppress the bone marrow. Hepcidin downregulates ferroportin (a protein that transports iron from inside the cell to the outside of the cell), decreases absorption of iron in the duodenum, and decreases the release of iron stores.

Activation of RAAS

The RAAS pathway is activated in response to decreased blood pressure and decreased sodium levels. 

Let’s review the RAAS pathway:

  • Renin is released
  • Renin cleaves angiotensinogen and converts it into angiotensin I
  • Angiotensin converting enzyme (ACE) converts angiotensin I into angiotensin II
  • Angiotensin II activates aldosterone
  • Aldosterone causes sodium and water retention
  • Intravascular volume and blood pressure are increased
  • Renal perfusion improves

Though helpful in improving cardiac output, chronic activation of RAAS can lead to cardiac remodeling and SNS activation, both of which can further worsen heart failure. Medications aimed at inhibiting RAAS (ACE inhibitors and ARBs) can decrease EPO levels and suppress the bone marrow’s response to EPO.

In addition, hemodilution secondary to RAAS activation can cause anemia as well.

Why is anemia a serious concern in heart failure?

Anemia is of concern in heart failure because it can lead to worsening heart function. 

  • Anemia causes tachycardia and increased stroke volume because the heart is having to work harder to compensate for the anemia. This increased workload on the heart can worsen heart failure.
  • Reduced renal blood flow and the resulting renal insufficiency occurs with anemia. This leads to fluid retention, which further stresses the heart and can eventually cause left ventricular hypertrophy and worsening heart failure. 

As you can see, heart failure and anemia are in a vicious cycle. Heart failure causes anemia, the anemia worsens the heart failure, and both conditions damage the kidneys, which worsens the anemia and the CHF. You may hear this cycle called the cardio renal anemia (CRA) syndrome. Unfortunately patients with CRA syndrome tend to be more resistant to heart failure medications and experience more frequent hospitalizations.

How is anemia in heart failure treated?

Because anemia in heart failure is associated with poorer outcomes, more frequent hospitalizations, and increased mortality, its treatment has been the subject of numerous studies. Various methods have been evaluated, including:

  • EPO stimulating agents (ESAs) – Though erythropoiesis-stimulating agents have shown to improve anemia in patients with chronic kidney disease, the research does not support their use in heart failure. Studies show that ESAs increase the risk for thromboembolic events and do not have a significant effect on mortality or hospitalization in patients with heart failure. At this time, ESAs are not recommended.
  • PRBC transfusion – Blood transfusion provides only short-term benefit for patients with severe anemia, and is not a suitable treatment for long-term management. 
  • Iron supplementation – Iron supplementation has shown to be a viable treatment for anemia in heart failure. Because patients with heart failure have increased levels of hepcidin (which decreases absorption of iron in the duodenum), IV supplementation has shown to be more effective than PO. 
  • Address contributing factors – Patients may receive medications or therapy for other factors that can contribute to anemia. This could include supplementation with vitamin B12 and/or folate, thyroid hormone replacement, and treatment of inflammatory co-morbidities.

I hope this brief summary helps you understand why patients with heart failure often have anemia and the challenges associated with its treatment.

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