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| REVIEW ARTICLE |
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| Year : 2021 | Volume
: 22
| Issue : 3 | Page : 196-200 |
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Anaemia in heart failure patients, associated with angiotensin – Renin – aldosterone system altering medications
Neda Jonaitiene, Grytė Ramantauskaitė, Jolanta Laukaitienė
Department of Cardiology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania, Europe, Lithuania
| Date of Submission | 01-Dec-2020 |
| Date of Acceptance | 25-Aug-2021 |
| Date of Web Publication | 11-Oct-2021 |
Correspondence Address:
Dr. Neda Jonaitiene
Department of Cardiology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania, Europe
Lithuania
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/HEARTVIEWS.HEARTVIEWS_211_20
 Abstract | | |
Heart failure (HF) remains one of the most common diseases and one of the major causes of death worldwide. HF is often associated with other chronic diseases, most commonly with anemia. Anemia increases patients' mortality and lowers their quality of life. There are a few pathophysiological mechanisms that explain anemia in patients with HF – hemodilution, absolute or functional iron deficiency, activation of the inflammatory cascade, chronic kidney disease, and impaired erythropoietin production and activity. Moreover, congestive HF is often treated with angiotensin-converting enzyme inhibitors and aldosterone receptors blockers, which could be linked to the development of anemia.
Keywords: Aldosterone receptors blocker, anemia, angiotensin-converting enzyme inhibitors, heart failure
How to cite this article:
Jonaitiene N, Ramantauskaitė G, Laukaitienė J. Anaemia in heart failure patients, associated with angiotensin – Renin – aldosterone system altering medications. Heart Views 2021;22:196-200 |
How to cite this URL:
Jonaitiene N, Ramantauskaitė G, Laukaitienė J. Anaemia in heart failure patients, associated with angiotensin – Renin – aldosterone system altering medications. Heart Views [serial online] 2021 [cited 2023 Sep 23];22:196-200. Available from: https://www.heartviews.org/text.asp?2021/22/3/196/328041 |
| Introduction | |  |
Heart failure (HF) remains one of the most common diseases and one of the major causes of death around the world.[1] HF is often associated with other chronic diseases, such as anemia, which increases patients' mortality and lowers their quality of life (QoL).[2] Furthermore, the incidence of anemia appears to be associated with the HF functional class worsening– from 9% for those with New York Heart Association (NYHA) class I HF, to 79% in those, with NYHA class IV HF.[3]
| Anaemia and Heart Failure | | |
Anemia in HF is complex and multifactorial. There are a few pathophysiological mechanisms that explain anemia in patients with HF such as hemodilution, absolute or functional iron deficiency, activation of the inflammatory cascade, chronic kidney disease (CKD), and impaired erythropoietin production and activity.[4]
Iron deficiency is very common in patients with congestive HF (CHF). It is worth mentioning that the incidence of iron deficiency is increases with the severity of HF.[3],[4] Iron deficiency for patients with CHF could be absolute or functional. There are many causes of absolute iron deficiency in CHF patients, especially in coexistence with CKD. It is associated with decreased iron stores and reduced deposits in the bone marrow that occurs because of poor dietary intake, impaired gastrointestinal absorption, chronic blood loss, and frequent removal of blood for tests. Functional iron deficiency is thought to be associated with increased hepcidin production and subsequent inhibition of the iron exporter ferroprotein that leads to impaired absorption and utilization of iron. They are both equally prevalent for patients with CHF.[2],[4]
Functional iron deficiency is related to iron disuse and iron acquisition by the reticuloendothelial system, as in the cases of other chronic diseases. For patients with severe CHF, the elevation of serum levels of several cytokines has been found, the most important of them: Interleukin-1 (IL-1), IL-6, tumor necrosis factor α (TNF-α), and IL-8. This activation of the inflammatory process reduces EPO production because of the activation of GATA2 binding protein and nuclear factor-κB. Impaired response to bone marrow erythroblasts also participates[4] in this process.
The activation of cytokines also causes hepcidin-induced blockade of iron absorption from the gut and iron retention in reticuloendothelial system's stores. Hepcidin is a protein induced by IL-6 and is excreted with urine. In cases of CHF with the coexisting presence of CKD, there is reduced hepcidin excretion, and its levels are increase. Hepcidin inhibits ferroportin, a protein, which regulates iron liberation from cells to the bloodstream, expressed on intestinal cells, macrophages, and hepatocytes. Because of that iron cannot be released from these cells into the blood. This causes inadequate iron delivery to the bone marrow erythroblasts and causes the functional iron deficiency. This occurs even though iron stores may be adequate. Moreover, hepcidin seems to have a direct inhibitory effect on the proliferation and survival of erythroblasts.[4]
Inflammatory cytokines may cause EPO resistance in anemic CHF patients. It is thought that there is a reduced responsiveness of erythroid cells to EPO, accompanied by increased levels of inflammatory cytokines (IL-6, TNF-α). Activation of these cells causes increased levels of blunted EPO and induces JAK-STAT signaling As mentioned before, hepcidin, which is induced by IL-6 has a direct inhibitory effect on erythroblast proliferation and survival and contributes to this process too.[4]
Nitrogen oxide (NO) plays a major role in contributing to anemia in CHF patients. Endothelial dysfunction, occurring in CHF patients, may disturb endothelial NO synthase activity and enhance myocardial dysfunction because of increased oxidative stress. NO also appears to have a direct inhibitory effect on bone marrow hematopoietic activity.[4] Of interest is that NO inhibits blood cell formation in nonischemic CHF, and inflammatory cytokines impair hematopoiesis in CHF following myocardial infarction in mice models.[5]
As mentioned before, another major factor contributing to anemia itself is kidney dysfunction. The renal damage in the CHF is mainly hypoxic due to reduced renal blood flow because of reduced ejection fraction. Hypoxia induces erythropoietin (EPO) production by peritubular fibroblasts. Renal dysfunction increases blunted EPO production in anemic patients with CHF. In this condition, both CKD and CHF cause increased reduction of blunted EPO, and resistance to EPO appears.[6] In addition, when there are both CHF and CKD, the kidney reduces EPO production and increases urinary loss of serum EPO and transferrin, which results in the progression of anemia.[4]
It leads us to angiotensin–renin–aldosterone system that involves both kidney and cardiac function. The angiotensin–renin–aldosterone system seems also to be involved in the control of erythropoiesis. Angiotensin II reduces renal blood flow, increases oxygen demands, and thereby stimulates erythropoietin production.[4],[7] This leads us to the medications that inhibit angiotensin, the renin aldosterone system. Usually, CHF is treated with angiotensin-converting enzyme (ACE) inhibitors and aldosterone receptors blockers (ARBs), which could be linked to the development of anemia too.[8]
| Angiotensin-Converting Enzyme Inhibitors and Its Relation with Anemia | | |
As mentioned above, ACE inhibitors are one of the baseline medications groups for HF patients. ACE inhibition is a sufficiently well-accepted treatment modality and mostly used for treating arterial hypertension, cardiovascular disease, or renal disease.[9] These medications, by inhibiting cardiac renin–angiotensin–aldosterone system (RAAS), by blocking the breakdown of bradykinins and through stimulating the synthesis of prostaglandins and nitric oxide, prevent LV hypertrophy, and dysfunction. ACE inhibitors also reduce sympathetic activity, improve endothelial function, decrease pro-inflammatory cytokines and prothrombotic factors, and stimulate fibrinolytic factors. All these mechanisms potentially contribute to the improvement of pulmonary, right ventricular, and skeletal muscle function.[10]
ACE inhibitors have plenty of side effects too. One of them is that they can cause anemia. Moreover, most ACE inhibitor side effects can be viewed as a class effect. As such, switching from one ACE inhibitor to another will not alleviate the side effect per se.[11] ACE inhibitors interfere with the RAAS, but their effect is not directly related to renin levels in the blood. ACE inhibitors blocks angiotensin-converting enzyme that converts angiotensin I to angiotensin II,[12] which cause decreased production of angiotensin II. Angiotensin II stimulates erythropoietin production and erythropoiesis by reducing oxygen delivery to erythropoietin-producing cells.[13] ACE inhibitors suppress the production of erythropoietin in a dose-dependent manner, which presents a particular problem when ACE inhibitors are administered in the presence of renal failure.[14]
It should be noted that in patients with HF plasma volume and erythropoietin levels are increased. Therefore, when ACE inhibitor therapy is started and plasma volume decreases, the anticipated hemoconcentration is not observed since RBC production has decreased in parallel.[15] The contribution of ACE inhibitors to erythropoiesis may be imperceptible in normal or near normal conditions, such as in uncomplicated hypertensive subjects with type 2 diabetes mellitus, but it is exaggerated when bone marrow requires all available stimuli to augment erythropoiesis, such as in patients with severe renal insufficiency, CHF, or immunosuppression.[16]
Clinical trials have shown a significant decrease in hemoglobin in patients treated with ACE inhibitors.[17] For example, treatment with enalapril was associated with an intent-to-treat model, with a rise in the risk of developing new anemia at 1 year by 56%.[18] The levels of an erythropoiesis inhibitor, N-acetylseryl-aspartyl-lysin-prolyn, rise with the usage of ACE inhibitor, causing inhibition of erythropoiesis and manifestation of anemia.[19] A subanalysis of the PAERI study comparing 3,361 patients with diabetic kidney disease with 1,861 patients with non-diabetic CKD found that the diabetic patients were treated more often with ACE inhibitors (73.9 vs. 55.4%, P < 0.0001) and had a higher prevalence of anemia (52.7 vs. 39.4%, P < 0.0001).[20]
| Angiotensin Receptor Blockers and Its Relation with Anaemia | | |
There is way less experience with ARBs in HF trials than it is with ACE inhibitors. However, several studies showed that ARBs produce hemodynamic, neurohormonal, and clinical effects similar to ACE inhibitors.[21] ARBs are receptor antagonists that block type 1 angiotensin II (AT1) receptors in blood vessels and other tissues such as the heart. The activation of AT1 receptors leads to vasoconstriction, stimulation of the release of catecholamines and antidiuretic hormone and promote growth of vascular and cardiac muscle.[22] Therefore, RAAS) activation represents a major pathway in the progression of HF, and as a consequence, a therapeutic target.
However, as already stated, angiotensin II stimulates erythropoietin production and erythropoiesis by reducing oxygen delivery to erythropoietin-producing cells. ACE inhibitors and ARBs reduce the amount of angiotensin II in the blood, may hamper erythropoietin production and its effect on the bone marrow.[18]
| Dual Renin–Angiotensin–Aldosterone System (Blockade | | |
Dual therapy of combining ACE inhibitor and ARB for total RAAS blockade should not be used for patients with CKD and hypertension regardless of whether they have diabetes.[23] Hard outcomes in large randomized trials did not indicate improvement, and complications occurred more often and were greater. These included hyperkalemia, hypotension, and acute kidney injury.[24],[25]
| Anemia Treatment in Patients with Heart Failure | | |
There is no single cause of anemia in HF. These include relative erythropoietin deficiency, erythropoietin resistance, malnutrition such as iron, folic acid, Vitamin B12 deficiency, or poor absorption of these substances due to gastrointestinal mucosal edema. Moreover, drugs used to treat patients with HF also have an effect on the development of anemia: ACE inhibitors and angiotensin receptor blockers may increase the levels of erythropoiesis inhibitors in the blood.
There are several options of anemia treatment in patients with HF, including oral iron supplementation, intravenous (IV) iron therapy, erythropoiesis-stimulating agents, and transfusion therapy.
| Transfusion Therapy | | |
In case of severe, symptomatic anemia, blood transfusion with packed red blood cells is often considered. However, data in patients with HF are limited. Transfusion therapy has only temporary benefits and additional risks in patients with HF such as volume overload and ischemic events.[26]
| Oral Iron Supplementation | | |
Oral iron supplements are frequently used for iron replacement therapy due to their relatively low cost and easy administration. However, gastrointestinal side effects are common. Moreover, the absorption of oral iron supplements from the gastrointestinal tract may be limited by many food products and medications and edema of the intestinal mucosa due to systemic venous congestion in HF patients.[27]
| Intravenous Iron Therapy | | |
Various IV iron complexes, such as ferric carboxymaltose, ferric hydroxide sucrose, ferric gluconate, and ferric hydroxide dextran, are available. Advantages of IV iron therapy include the small number of injections required, rapid improvement in iron parameters,[28] and the cost-effectiveness, probably due to improved QoL and reduced HF hospitalizations.[29]
FAIR-HF, CONFIRM-HF clinical trials showed us that treatment with IV iron carboxymaltose not only improved patients' functional status and QoL but also reduced the risk of repeated inpatient treatment and death due to exacerbation of HF.[28],[30] The positive effects of IV iron have also been described in the clinical trial FERRIC-HF by Okonko DO. Patients treated with IV iron had a reduction in HF symptoms, improvement of exercise tolerance, and cardiac ultrasound parameters compared with placebo.[31]
| Erythropoiesis Stimulating Agents | | |
The use of erythropoiesis-stimulating agents (ESA) such as erythropoietin and its derivatives was recently debated. The RED-HF trial seems to demonstrate a neutral or even negative effect while treating anemia with darbepoetin. Some cardiac and systemic conditions (i.e., hypertension, atrial fibrillation, and prothrombotic status) may predispose to adverse events, and ESA administration should be avoided. High-dosage and chronic administration should be avoided[32] to prevent the negative effects.
| Conclusions | | |
It is well known that HF often leads to anemia due to a large variety of pathological mechanisms, especially when HF is related to CKD. As mentioned before, it is not only the pathogenesis of HF that provokes anemia, but also medications used to treat HF. This effect of medications interfering with angiotensin (renin-aldosterone system) should be considered for HF patients who already has severe anemia that is resistant to treatment. Furthermore, the treatment of anemia in HF patients should be considered too, as there is a possibility to make patients QoL much better.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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