Levels of Hematopoiesis Inhibitor N -Acetyl-Seryl-Aspartyl-Lysyl-Proline Partially Explain the Occurrence of Anemia in Heart Failure

Abstract

Background— Anemia is common in patients with chronic heart failure (CHF) and is associated with a poor prognosis. However, only a minority of patients with CHF have impaired renal function or underlying hematinic deficiencies. It has been shown that inhibition of the renin-angiotensin system is associated with the development of anemia. The aim of the present study was to determine possible mechanisms linking anemia to renin-angiotensin system activity in CHF patients. Methods and Results— We initially evaluated 98 patients with advanced stable CHF who were treated with ACE inhibitors (left ventricular ejection fraction, 28±1%; age, 69±1 years; 80% male), 10 of whom had an unexplained anemia (normal hematinics and no renal failure). These 10 anemic patients were matched with 10 nonanemic patients in terms of age and left ventricular ejection fraction. Serum ACE activity was 73% lower in anemic CHF patients compared with nonanemic CHF patients ( P =0.018). Moreover, serum of these patients inhibited in vitro the proliferation of bone marrow–derived erythropoietic progenitor cells of healthy donors by 17% ( P =0.003). Levels of the hematopoiesis inhibitor N -acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), which is almost exclusively degraded by ACE, were significantly higher in anemic CHF patients and were clearly correlated to erythroid progenitor cell proliferation ( r =−0.64, P =0.001). Conclusions— Serum ACE activity is markedly lower in anemic CHF patients, and serum of these patients inhibits hematopoiesis. The clear correlation between Ac-SDKP and proliferation of erythroid progenitor cells suggests an inhibitory role of Ac-SDKP on hematopoiesis in CHF patients, which may explain the observed anemia in patients treated with ACE inhibitors.

Inhibition of the Renin Angiotensin System during Autologous Stem Cell Transplant Does Not Impact Time to Engraftment

“…AcSDKP inhibits proliferation of hematopoietic pluripotent stem cells and blocks response of hematopoietic cells to proliferative stimuli in vitro [8]. However, AcSDKP is likely not the sole effecttor of the RAS on hematopoiesis, as animal models demonstrate that infusions of angiotensin II can correct anemia in ACE-deficient mice [9].…”

Anaemia and heart failure

“…Moreover, ACE catalyzes the demolition of N-Acetil-serillisil-proline (Ac-SKPD), a tetra peptide inhibitor of the proliferation of haematopoietic stem cells. ACE inhibitor administration causes an increase in the plasmatic concentrations of this substance with a consequent development of anaemia [30].…”

Approaches to the treatment of anaemia in patients with chronic heart failure

“…Surprisingly, although we know much about the prevalence and prognostic importance of anaemia in these patients, we know very little about its causation. We think the aetiology of anaemia in CHF is multifactorial, with impaired iron metabolism, bone marrow suppression by pro-inflammatory cytokines, inadequate erythropoietin production and blunted response to erythropoietin in the bone marrow among the suspected culprits [6,10,[16][17][18][19][20][21][22]. Other potential candidates include renal dysfunction, salt and water retention causing haemodilution and the use of drugs such as antiplatelet and anticoagulant agents which increase the risk of blood loss from the gastrointestinal tract [6,10,[16][17][18][19][20][21][22].…”

“…This mismatch between erythropoietin and haemoglobin may be because erythropoietin production is impaired in CHF or because there is erythropoietin resistance in the bone marrow (or both) [6,10,[16][17][18][19][20][21][22]. The chronic renal impairment that often accompanies CHF may also play a role, as a part of the pathophysiological ''vicious cycle'' that has been named the cardio-renal-anaemia syndrome [29].…”

“…Iron deficiency in patients with CHF probably has several aetiological factors including poor dietary intake, malabsorption due to oedema of the bowel wall, blood loss from the gastrointestinal tract as a result of antiplatelet and anticoagulant medication, uraemic gastritis and defective mobilisation of iron due to cytokine activation and the hepatic peptide hepcidin [6,10,[16][17][18][19][20][21][22]41].…”