European Heart Journal Advance Access originally published online on September 11, 2008
European Heart Journal 2008 29(21):2695; doi:10.1093/eurheartj/ehn399
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Erythropoietin, haemoglobin, heart failure, and mortality
Hypertension, Nephrology, Dialysis and Transplantation
Auburn University
Suite 3
2609 Village Professional Drive
Opelika, AL 36801
USA
Tel: +11 334 749 6523
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Email: hndt512{at}bellsouth.net
I would like to congratulate Dr van der Meer and his colleagues for their work on their evaluation of the relationship of haemoglobin, endogenous erythropoietin (EPO) levels and increased mortality in patients with congestive heart failure.1 Since we have been involved in evaluation of EPO levels in patients with renal failure for the last quarter of a century, 2,3 allow me to add possible alternative explanations to bone marrow resistance that could possibly explain their data.
In renal failure, there is very little correlation between, endogenous EPO levels and haemoglobin levels.2–6 Oxygen delivery regulates EPO production rather than haemoglobin level.7 A transcriptional factor known as hypoxia inducible factor (HIF) is rapidly destroyed by well-oxygenated cells through ubiquitylation by the von Hippel–Lindau tumour suppressor (pHVL) E3 ligase;8 however, when oxygen delivery decreases, pHVL no longer executes proteolysis of HIF and EPO production is increased. Once it is appreciated that EPO is normally regulated by oxygen delivery rather than haemoglobin level, one realizes that metabolic derangements such as acidosis, hypocapnia, and hyperphosphataemia can shift the oxygen–haemoglobin dissociation curve and change oxygen delivery and consequently EPO levels.9 Therefore patients with congestive heart failure and hyperventilation who develop either respiratory alkalosis or a metabolic acidosis from poor tissue perfusion would shift their oxygen–haemoglobin dissociation curves and EPO production in one direction while patients with the same haemoglobin levels but with metabolic alkalosis due to diuretics would shift EPO production in the opposite direction. Since receptor (EPOR) affinity may also change, we have found it probably too simplistic to assume that a particular EPO level will produce a certain haemoglobin level in the face of metabolic perturbations even when we can control the EPO levels.10,11
Finally, angiotensin (AII) is well known to stimulate EPO production,12 while the inhibition of AII is associated with EPO resistance. It is theoretically possible that elevated AII levels may have been responsible for both the mortality and EPO differences that Dr van der Meer has found. Both EPO and AII have similar tyrosine kinase receptors that may have evolved from primitive adhesion molecules.7 Although there was no significance difference in the number of patients using AII converting enzyme inhibitors or AII receptor blockers, Dr van Meer gives no data on AII. Higher than expected EPO levels may have been from higher than expected AII levels which are already known to be associated with abnormal vascular remodelling and increased mortality. Furthermore since EPO is known to increase intimal hyperplasia,13 one might be wary of prospective studies that administer exogenous EPO to patients with known cardiac disease. Therefore, while the data of Dr van der Meer add significantly to our understanding and the authors are certainly correct that cytokines and inflammation might be a unifying hypothesis, I would urge caution in attributing the sole cause as reduction bone marrow sensitivity at present and I look forward to their further work in this area.
References
- van der Meer P, Lok DJ, Januzzi JL, de la Porte PW, Lipsic E, van Wijngaarden J, Voors AA, van Gilst WH, van Veldhuisen DJ. Adequacy of endogenous erythropoietin levels and mortality in anaemic heart failure patients. Eur Heart J (2008) 29:1510–1515.
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- Diskin CJ. Hitting the target but missing the goal? Hemoglobin targets versus oxygen delivery. Am J Kidney Dis (2007) 50:344.[Web of Science][Medline]
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[Abstract/Free Full Text]
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