7/31/2019 Am J Physiol Heart Circ Physiol-2009-Gao-H559-60
2/3
Editorial Focus
Is erythropoietin behind maladaptive anemic heart failure?
Erhe Gao and Walter J. Koch
George Zallie and Family Laboratory for Cardiovascular Gene
Therapy, Center for Translational Medicine, and Department
of Medicine, Thomas Jefferson University, Philadelphia,
Pennsylvania
HEART FAILURE (HF) is a major public health problem world-wide.
HF is a syndrome arising from multiple causes that willaffect one
in five adults in their lifetime. Despite the progressthat has been
made in the treatment of chronic HF, the overallmorbidity and
mortality remain high (8). Therefore, it isimperative that there is
a continued push to more fully under-stand the molecular mechanisms
responsible for this disease todiscover and develop novel
therapies. Among the multiplecharacteristics of chronic HF, anemia,
defined by the WorldHealth Organization criteria as a hemoglobin
(Hb) concentra-tion of13 g/dl in adult men and 12 g/dl in adult
women, isfound in 30% to 40% of cases and is an independent risk
factorfor more severe HF (1, 2, 12, 17).
When compared with HF patients with normal Hb levels,
thepresence of anemia is associated with worsened clinical
symp-toms, more severe systolic and diastolic dysfunction, and
asignificant increase in mortality in patients with advanced HF(4,
6, 7, 17). Moreover, these patients have higher brainnatriuretic
peptide levels, increased extracellular and plasmavolume, and more
rapid deterioration of renal function. It hasbeen shown that
chronic untreated anemia can result in in-creased cardiac output
that eventually can lead to ventriculardilation, increased left
ventricular (LV) mass, and the devel-opment of LV hypertrophy,
which represent cardiac remodel-ing parameters that are strong
predictors of morbidity andmortality (12). Understanding how
chronic anemia leads to LVremodeling and poorer outcomes in HF is
essential to improve
how we may treat these large number of patients with HF.Naito
and colleagues (12a) report an animal model of
chronic anemia that leads initially to an adaptive phase
ofpreserved cardiac function despite LV remodeling followedover
time by maladaptation and severe LV dysfunction. Thecompensatory
phase followed by decompensation appears tocorrelate with the
dynamic regulation of serum erythropoietin(EPO) levels and cardiac
EPO signaling. This study under-scores the significance of cardiac
EPO-EPO receptor (EPO-R)signaling as a cardioprotective axis.
EPO, a hematopoietic cytokine that is primarily synthesizedin
kidney peritubular cells in response to hypoxia, has longbeen used
as a clinical treatment for conditions of low Hb. The
physiological effects of EPO in hematopoietic cells are
medi-ated through its interaction with its specific cellular
receptor,EPO-R, a member of the type I superfamily of
single-trans-membrane cytokine receptors (3, 9). Recently, data
have ac-cumulated demonstrating that the EPO-R is present in a
varietyof other tissues outside the blood, including
cardiomyocytes,suggesting the potential roles of EPO signaling
beyond hema-topoiesis and the treatment of anemia (20).
Recombinant-
human EPO administration has been shown to exert a
broadtissue-protective effect in a variety of experimental models.
Inthe cardiovascular system, EPO has been shown to exertmarked
myocardial protective effects against ischemia-reper-fusion injury
via a reduction of LV infarct size and a signifi-cantly decreased
apoptotic cell death of cardiomyocytes, whichleads to an enhanced
recovery of LV function (5, 16). Mech-anistically, studies have
shown that EPO-EPO-R signaling canstimulate the JAK/STAT, MAPK, and
phosphatidylinositol3-kinase/Akt signaling pathways in cardiac
cells, much like thesignaling in hematopoietic cells (13, 14).
Cardioprotectionafter ischemic injury characterized by increased
angiogenesisin the heart has also been found using darbepoetin-, a
longer-
acting synthetic EPO analog (11, 18). In apparent support ofthe
cardioprotective actions of EPO and analogs, recent clinicaltrials
have shown that in anemic patients with HF, EPOtreatment increases
and maintains Hb and LV ejection fractionwith improved
quality-of-life scores and exercise duration (10,15, 19). However,
the mechanism of these beneficial effects ofEPO in patients with
anemic HF has not been fully understoodor clarified.
In the study by Naito et al. (12a), important mechanismsbehind
the adaptive and maladaptive responses of the heart toa long-term
anemia induced by iron deficiency have beenuncovered. First, they
demonstrate in rats that iron deficiencyanemia (IDA) leads to
cardiac hypertrophy at 12 wk with amaintained cardiac output.
However, after 20 wk of IDA, serial
echocardiographic measurements revealed significant
cardiacdysfunction characterized at the end of the study by an
increasein the LV weight-to-tibia length ratio and the lung wet
weight-to-lung dry weight ratio. Moreover, at a molecular level,
atrialnatriuretic peptide, brain natriuretic peptide, and collagen
type3 gene expressions were increased, consistent with the
myo-cardial interstitial fibrosis that was evident in IDA rats.
Inter-estingly, circulating levels of EPO were inversely
correlatedwith these phenotypic findings, with upregulation at 12
wk anda significant decrease at 20 wk, suggesting a change in
EPO-EPO-R signaling in the late-stage HF induced by IDA.
This study revealed some potentially important
mechanisticfindings implicating STAT3 activation as a culprit in
IDA-
induced maladaptation. Of note, serum EPO levels and
thephosphorylation of STAT3 peaked at 12 wk and
subsequentlydecreased at 20 wk, raising the possibility that a
compensatoryand decompensatory EPO-EPO-R signaling mechanism
mayexist in the hearts of rats with chronic IDA (12a).
Consistentwith this, a previous study has showed that activated
(i.e.,phosphorylated) STAT3 can occur in cardiac cells
stimulatedwith EPO (14). Importantly, to further explore whether
thepreservation of increased EPO levels is associated with
adap-tive cardiac remodeling, Naito et al. (12a) evaluated the
cardiaceffects of EPO therapy on rats after they had been on
aniron-deficient diet for 12 wk. EPO administration attenuatedthe
downregulation of cardiac STAT3 phosphorylation and
Address for reprint requests and other correspondence: W. J.
Koch, Centerfor Translational Medicine, George Zallie and Family
Laboratory for Cardio-vascular Gene Therapy, Thomas Jefferson
Univ., 1025 Walnut St., Rm. 317,Philadelphia, PA 19107 (e-mail:
[email protected]).
Am J Physiol Heart Circ Physiol 296: H559H560,
2009;doi:10.1152/ajpheart.00045.2009.
0363-6135/09 $8.00 Copyright 2009 the American Physiological
Societyhttp://www.ajpheart.org H559
7/31/2019 Am J Physiol Heart Circ Physiol-2009-Gao-H559-60
3/3
prevented cardiac dysfunction in the IDA group. Meanwhile,blood
Hb and systolic blood pressure were not altered in theIDA group
receiving EPO. Increasing EPO levels in these ratsclearly prevented
the transition from adaptive cardiac hyper-trophy to maladaptive LV
remodeling and HF even withsustained IDA. Accordingly, the study
implicates STAT3 ac-tivation to be critical for the EPO-dependent
maintenance of
LV function despite IDA.Overall, this study underscores the
importance of maintain-
ing EPO levels in HF patients and may open up a newtherapeutic
window to use this cardioprotective cytokine morefrequently, even
in patients without anemia. Of course, furtherstudies, especially
in larger animals and different models ofHF, are warranted since
EPO can increase the risk of throm-botic events. Nevertheless,
Naito et al. (12a) have shed newlight on this interesting
field.
REFERENCES
1. Anand I, McMurray JJ, Whitmore J, Warren M, Pham A,
McCamishMA, Burton PB. Anemia and its relationship to clinical
outcome in heartfailure. Circulation 110: 149154, 2004.
2. Anand IS. Anemia and chronic heart failure implications and
treatmentoptions. J Am Coll Cardiol 52: 501511, 2008.
3. Constantinescu SN, Ghaffari S, Lodish HF. The erythropoietin
receptor:structure, activation and intracellular signal
transduction. Trends Endocri-nol Metab 10: 1823, 1999.
4. Ezekowitz JA, McAlister FA, Armstrong PW. Anemia is common
inheart failure and is associated with poor outcomes: insights from
a cohortof 12 065 patients with new-onset heart failure.
Circulation 107: 223225,2003.
5. Gao E, Boucher M, Chuprun JK, Zhou RH, Eckhart AD, Koch
WJ.Darbepoetin alfa, a long-acting erythropoietin analog, offers
novel anddelayed cardioprotection for the ischemic heart. Am J
Physiol Heart CircPhysiol 293: H60H68, 2007.
6. Groenveld HF, Januzzi JL, Damman K, van Wijngaarden J,
HillegeHL, van Veldhuisen DJ, van der Meer P. Anemia and mortality
in heartfailure patients a systematic review and meta-analysis. J
Am Coll Cardiol52: 818827, 2008.
7. Horwich TB, Fonarow GC, Hamilton MA, MacLellan WR,
Boren-stein J. Anemia is associated with worse symptoms, greater
impairment infunctional capacity and a significant increase in
mortality in patients withadvanced heart failure. J Am Coll Cardiol
39: 17801786, 2002.
8. Levy D, Kenchaiah S, Larson MG, Benjamin EJ, Kupka MJ, Ho
KK,Murabito JM, Vasan RS. Long-term trends in the incidence of
andsurvival with heart failure. N Engl J Med 347: 13971402,
2002.
9. Maiese K, Li F, Chong ZZ. New avenues of exploration for
erythropoi-etin. JAMA 293: 9095, 2005.
10. Mancini DM, Katz SD, Lang CC, LaManca J, Hudaihed A,
AndroneAS. Effect of erythropoietin on exercise capacity in
patients with moderateto severe chronic heart failure. Circulation
107: 294299, 2003.
11. Boucher M, Pesant S, Lei YH, Nanton N, Most P, Eckhart AD,
KochWJ, Gao E. Simultaneous administration of insulin-like growth
factor-1and darbepoetin alfa protects the rat myocardium against
myocardialinfarction and enhances angiogenesis. Clinical and
Translational Science1: 1320, 2007.
12. Mitchell JE. Emerging role of anemia in heart failure. Am J
Cardiol 99:15D20D, 2007.12a.Naito Y, Tsujino T, Matsumoto M, Sakoda
T, Ohyanagi M, Ma-
suyama T. Adaptive response of the heart to long term anemia
induced byiron deficiency. Am J Physiol Heart Circ Physiol (January
9, 2009).doi:10.1152/ajpheart.00463.2008.
13. Parsa CJ, Kim J, Riel RU, Pascal LS, Thompson RB, Petrofski
JA,Matsumoto A, Stamler JS, Koch WJ. Cardioprotective effects of
eryth-ropoietin in the reperfused ischemic heart: a potential role
for cardiacfibroblasts. J Biol Chem 279: 2065520662, 2004.
14. Parsa CJ, Matsumoto A, Kim J, Riel RU, Pascal LS, Walton
GB,Thompson RB, Petrofski JA, Annex BH, Stamler JS, Koch WJ. Anovel
protective effect of erythropoietin in the infarcted heart. J
Clin
Invest 112: 9991007, 2003.15. Ponikowski P, Anker SD,
Szachniewicz J, Okonko D, Ledwidge M,
Zymlinski R, Ryan E, Wasserman SM, Baker N, Rosser D, Rosen
SD,
Poole-Wilson PA, Banasiak W, Coats AJ, McDonald K. Effect of
darbepoetin alfa on exercise tolerance in anemic patients with
symptom-atic chronic heart failure: a randomized, double-blind,
placebo-controlledtrial. J Am Coll Cardiol 49: 753762, 2007.
16. Rastogi S, Imai M, Sharov VG, Mishra S, Sabbah HN.
Darbepoetin-prevents progressive left ventricular dysfunction and
remodeling in non-anemic dogs with heart failure. Am J Physiol
Heart Circ Physiol 295:H2475H2482, 2008.
17. Silverberg DS, Wexler D, Iaina A, Schwartz D. The
interaction betweenheart failure and other heart diseases, renal
failure, and anemia. Semin
Nephrol 26: 296306, 2006.18. van der Meer P, Lipsic E, Henning
RH, Boddeus K, van der Velden
J, Voors AA, van Veldhuisen DJ, van Gilst WH, Schoemaker RG.
Erythropoietin induces neovascularization and improves cardiac
functionin rats with heart failure after myocardial infarction. J
Am Coll Cardiol 46:125133, 2005.
19. van Veldhuisen DJ, Dickstein K, Cohen-Solal A, Lok DJ,
Wasserman
SM, Baker N, Rosser D, Cleland JG, Ponikowski P.
Randomized,double-blind, placebo-controlled study to evaluate the
effect of two dosingregimens of darbepoetin alfa in patients with
heart failure and anaemia.
Eur Heart J 28: 22082216, 2007.20. Wright GL, Hanlon P, Amin K,
Steenbergen C, Murphy E, Arcasoy
MO. Erythropoietin receptor expression in adult rat
cardiomyocytes isassociated with an acute cardioprotective effect
for recombinant erythro-poietin during ischemia-reperfusion injury.
FASEB J 18: 10311033,2004.
Editorial Focus
H560
AJP-Heart Circ Physiol VOL 296 MARCH 2009 www.ajpheart.org
http://dx.doi.org/10.1152/ajpheart.00463.2008http://dx.doi.org/10.1152/ajpheart.00463.2008http://dx.doi.org/10.1152/ajpheart.00463.2008http://dx.doi.org/10.1152/ajpheart.00463.2008http://dx.doi.org/10.1152/ajpheart.00463.2008http://dx.doi.org/10.1152/ajpheart.00463.2008
![Preeti Ahuja, Patima Sdek and W. Robb MacLellanweb.mit.edu/smik/www/521.pdf · [Abstract]€ [Full Text]€ Am J Physiol Heart Circ Physiol, September 1,€2007; 293€(3): H1883-H1891](https://img.pdfslide.us/doc/110x75/5fb5dde71723a8374a613be1/preeti-ahuja-patima-sdek-and-w-robb-abstracta-full-texta-am-j-physiol.jpg)
![Am J Physiol Heart Circ Physiol 2011[1]](https://img.pdfslide.us/doc/110x75/577ce0031a28ab9e78b28109/am-j-physiol-heart-circ-physiol-20111.jpg)
