“The adverse cardiovascular effects of anemia in chronic kidney disease

have been well established. New data are now emerging to suggest this
condition may represent an important treatable cause of cardiac
morbidity and mortality in patients with heart failure as well.”

III Anemia&
Cardiovascular
Disease
Key Points

• Anemia is a common condition that may promote

or exacerbate cardiovascular disease (CVD).
• Low Hb and Hct values are associated with
increased CVD morbidity and mortality in
patients with end-stage renal disease and
congestive heart failure (CHF).
• Clinical studies suggest that regression of
left ventricular hypertrophy is possible with
correction of anemia.
• Early evidence suggests that correction of anemia
may improve exercise capacity and decrease
adverse outcomes in patients with CHF.
• Anemia is common in elderly patients hospitalized
with acute myocardial infarction, and transfusion
may improve outcome.
Anemia pdf revised•.qxd 6/13/02 12:18 AM Page 20
20
Anemia and Cardiac Risk
Hypertension is well recognized for its
role not only as an etiologic factor for
cardiovascular diseases, such as myocar-
dial infarction and angina, but also for its
ability to aggravate the course of many
established cardiovascular diseases. Early
diagnosis and aggressive treatment of
hypertension at any point has become a
critical component in the prevention and
management of cardiac disease. Anemia,
which is often untreated or inadequately
treated, is emerging as another potential-
ly common contributor to the develop-
ment and progression of cardiovascular
disease (CVD).1 Although the complete
picture of anemia’s role in CVD is cur-
rently unknown, hemodynamic changes
brought about by this condition have
cardiovascular consequences that could
both predispose toward and aggravate
existing cardiac disease.
Anemia and Cardiac Pathophysiology
Anemia provokes a series of cardio-
vascular alterations that may result in a
compensatory increase in cardiac output
and blood flow in the short term. These
initially favorable adaptations, however,
may lead to cardiac structural changes,
which could predispose to CVD over
time.2,3 For patients with known CVD,
anemia may be particularly problematic.
It is well established that anemia has
adverse effects on myocardial oxygena-
tion that result in the provocation or
acceleration of angina, and anemia may
worsen congestive heart failure (CHF).4
Inadequate tissue oxygenation result-
ing from anemia appears to be the initial
trigger for a number of specific hemody-
namic adjustments.5,6 Systemic arterial
dilatation leads to decreased systemic
Anemia: A Hidden Epidemic
vascular resistance and reduced afterload,
which may improve stroke volume.7
Anemia decreases blood viscosity, which
may improve venous return and thus
augment preload. Anemia also activates
the sympathetic nervous system, which
induces an increase in heart rate.8 These
changes in the heart and circulation act
to raise cardiac output in the short term.
In contrast, over the long term, adap-
tations that initially increase cardiac out-
put may lead to left ventricular enlarge-
ment and left ventricular hypertrophy
(LVH). These two forms of cardiac
remodeling predispose to heart failure
and may aggravate coronary artery dis-
ease. The sustained sympathetic activa-
tion that accompanies anemia may be
particularly problematic when accompa-
nied by ventricular enlargement and
LVH. Sympathetic activation is now
Reduced hemoglobin
Tissue hypoxia
Increased cardiac work
Neurohormonal activation
Left venticular Ischemic heart
hypertrophy disease
Worsening or precipitation of:
Congestive heart failure
Arrhythmias
Angina pectoris
Myocardial infarction
Figure 3-1. Adverse cardiovascular effects
of anemia.
III. Anemia & Cardiovascular Disease
recognized to play a major role in the
pathophysiology of heart failure and beta
blockade has emerged as a major form
of therapy for this syndrome.9,10
Chronic anemia may have adverse
effects on the vasculature as well. Arterial
hypertrophy and remodeling may occur
as a result of sustained increases in car-
diac output. This may reverse the early
vasodilation characteristic of anemia and
lead to increased systemic vascular resis-
tance, which further contributes to the
development of LVH and poor cardiac
function. Early on these changes may be
reversible; however, in conditions such
as chronic kidney disease (CKD), they
may become permanent.5
Anemia and Cardiac
Morbidity and Mortality
The adverse cardiovascular effects of
anemia in (CKD) have been well estab-
lished. New data are now emerging to
suggest this condition may represent an
important treatable cause of cardiac mor-
bidity and mortality in patients with heart
failure as well. Anemia also appears to
contribute to the development of cardiac
symptoms in cancer patients.
CKD
The relationship between anemia and
CVD has been well established in
patients with CKD. Two studies in
patients with predialysis CKD, conducted
by Levin and colleagues, demonstrated
that anemia is an independent risk factor
for the development of LVH. Specifically,
decreasing Hb was associated with
increasing risk of LVH. The first study
showed a 6% increase in the risk of LVH
for each 1 g/dL decrease in Hb.11 The
second, larger study showed an even
21
greater risk: an increase of 32% in LVH
risk for each 0.5-g/dL decrease in Hb
(P = 0.004).2 This study identified three
risk factors that contributed to the devel-
opment of LVH in patients with CKD: Hb
concentration, systolic blood pressure,
and baseline left ventricular mass index.
Similarly, in patients with end-stage renal
disease (ESRD) undergoing dialysis, left
ventricular end-diastolic volume and left
ventricular mass both were found to
increase with decreasing Hb levels.12
Decreasing Hb levels have also been
associated with a greater risk of the
development of de novo or recurrent
heart failure and increased mortality in
this population.3
Collins and colleagues, in their study
of nearly 67,000 ESRD patients starting
dialysis, demonstrated that lower Hct is
associated with higher cardiac-related
hospitalizations and mortality at 1 year.13
Patients with Hct <30% or 30% to <33%
were found to have a significantly higher
risk of cardiac death than patients with
Hct ≥33% to <36% at 1 year [RR 1.74
(95% CI, 1.66-1.83) and RR 1.25 (95% CI,
1.20-1.30), respectively]. The risk of car-
diac-related hospitalization was also sig-
nificantly higher in patients with Hct
<30% or 30% to <33% than in those with
Hct ≥33% to <36% [RR 1.3 (95% CI, 1.21-
1.38) and RR 1.17 (95% CI, 1.11-1.18),
respectively]. Interestingly, those with
Hct ≥36% to <39% had even lower car-
diac-hospitalization risk than did those in
the benchmark ≥33% to <36% Hct group
(RR, 0.75; 95% CI, 0.71-0.82).
CHF
In the last two decades, CHF has
become a serious public health problem
in western industrialized countries, and
22
its prevalence continues to increase
throughout the world. An estimated 5
million patients currently suffer from this
condition in the United States, with
approximately 400,000 new cases report-
ed annually.14-16 Despite treatment
advances, CHF is associated with a high
rate of morbidity and mortality.17-19
The incidence and prevalence of ane-
mia in CHF patients cannot be precisely
determined from existing data, but retro-
spective studies suggest that reduced Hb
is common in this syndrome. Patients
hospitalized with CHF have been report-
ed to have a mean Hb level of approxi-
mately 12 g/dL, and it has been demon-
strated that the Hb level decreases as the
severity of heart failure progresses.16,17 For
example, a retrospective analysis of 142
patients with CHF revealed that the
prevalence of a Hb level <12 g/dL
increased with the severity of the dis-
ease, reaching a prevalence of 79.1% in
patients with New York Heart Association
(NYHA) functional classification IV.20 In
addition, endogenous erythropoietin lev-
els have been shown to increase with
increasing severity of CHF.16,18,19
Several potential mechanisms have
been proposed to explain the relationship
between anemia and CHF. Heart failure is
often complicated by impaired renal func-
tion, which may result in decreased pro-
duction of endogenous erythropoietin.
Some evidence suggests that low cardiac
output, especially likely in severe CHF,
may impair bone marrow function.21 For
example, a recent report using a mouse
model demonstrated a 40% to 50% reduc-
tion in progenitor cells in the bone mar-
row of animals with infarcts, which
appeared to be due to apoptosis, possibly
induced by cytokines.22
Anemia: A Hidden Epidemic
Another potential mechanism is right-
sided heart failure with passive conges-
tion, which may cause sufficient malab-
sorption and nutritional deficits to result
in reduced Hb.23 The use of angiotensin-
converting enzyme inhibitors, while
important in heart failure management,
may inhibit the synthesis of endoge-
nous erythropoietin.24 Additionally, a
systemic inflammatory state with activa-
tion of cytokines is increasingly recog-
nized as an important part of the mal-
adaptive neurohormonal activation that
occurs in CHF. Cytokines and other
mediators of this systemic inflammatory
response may be involved in the devel-
opment and progression of anemia.
Finally, the increased levels of unbound
iron seen in anemia can theoretically
catalyze the peroxidation of lipids, thus
enhancing oxidative stress and proin-
flammatory responses and potentially
aggravating anemia.25
Epidemiological data from several
large heart failure clinical trials have
demonstrated an association between
anemia and adverse outcomes in this
syndrome. Lower Hct and Hb values in
patients with CHF have been associated
with increased mortality risk. A recent
retrospective analysis of the Studies of
Left Ventricular Dysfunction (SOLVD) trial
showed that in several thousand patients,
reduced Hct was an independent risk
factor for mortality.26 A retrospective
cross-sectional analysis of 1,734 patients
with advanced CHF, referred to UCLA
Medical Center between 1983 and 1999,
confirmed an inverse correlation between
Hb level and mortality. In addition, a
lower Hb level is associated with a
greater need for urgent status for heart
transplantation.27
III. Anemia & Cardiovascular Disease
Acute Myocardial Infarction
Many treatment advances have
improved outcome in acute myocardial
infarction (AMI), but this disease contin-
ues to have a high mortality risk in the
elderly. The potential for anemia to
worsen AMI outcome is clear, but the
frequency and impact of reduced Hct in
this condition had not been well investi-
gated until the recent work of Wu and
colleagues.28 These investigators noted a
strong adverse association between 30-
day mortality and admission Hct in a ret-
rospective study of 78,984 Medicare ben-
eficiaries ≥65 years. Both adjusted and
unadjusted analysis suggested that
patients with admission Hct values of
39.1% to 48% had a substantially lower
30-day mortality rate than did patients
with lower admission Hct values. For
example, the 30-day survival rate was
82.8% in patients with the highest admis-
sion Hct values, 70% for patients with
admission Hct values of 30.1% to 33.0%,
and 64.1% for patients with admission
Hct values of 27.1% to 30%. In addition,
anemia sufficient to affect prognosis was
found to be much more common than
previously reported. By the criteria of
Hct <39%, 43.4% were anemic, and 4.2%
had Hct <30%. These findings suggest
that anemia may be an important and
underrecognized risk factor in patients
with AMI.29
Cancer
Symptomatic cardiovascular disease is
not uncommon in patients with cancer.
Signs and symptoms of cardiac disease in
patients with cancer include exertional
dyspnea, tachycardia, palpitations, and
increased pulse pressure.30 Structural
changes, namely cardiac enlargement and
23
eccentric hypertrophy, have also been
reported. Anemia is common in patients
with cancer and appears to play a major
role in the development of cardiac symp-
toms in patients with malignancy. The
severity of these symptoms is dependent
not only on the degree of anemia but
also on other patient characteristics, such
as age, type of malignancy, and underly-
ing pulmonary and cardiac function.30
Beneficial Effects of
Anemia Management
CKD
A number of favorable cardiovascular
effects have been observed in patients
with CKD whose anemia has been treat-
ed. A recent report by London and col-
leagues demonstrated that treatment
directed toward lowering blood pressure
and reversing anemia was associated
with a reduction in left ventricular mass
and favorable outcomes during long-term
follow-up in a cohort of 153 patients
receiving dialysis.31 Augmentation of Hct
to within the normal range, target 40%,
was associated with significant reductions
in left ventricular mass index (LVMI), a
measure of LVH, that were superior to
those observed with partial anemia cor-
rection, target 30% (P <0.01).32 The rela-
tionship between anemia treatment and
improvements in LVMI was also observed
in several small studies that used Hb as a
measure of anemia.33-36
Treatment of anemia in ESRD patients
undergoing dialysis has also been associ-
ated with improvements in myocardial
ischemia. Results of a small study con-
ducted by Wizemann and colleagues
showed that correction of Hct from 25%
to 35% led to an 81% reduction in
24
ST-segment depression during stress test-
ing, as well as to significant increases in
exercise duration (mean 362 s to 489 s,
P <0.01) and maximum workload
achieved (mean 79 W to 104 W, P <0.01).37
CHF
Preliminary studies show that correction
of mild anemia in patients with severe
CHF has beneficial effects. In an uncon-
trolled study, Silverberg and colleagues
used a combination of subcutaneous epo-
etin (mean dose 5,227 IU/week) and
intravenous iron (mean dose 185.1
mg/week) to correct anemia in 26 patients
with persistent, severe heart failure (all
NYHA class III or IV).38 Treatment resulted
in improvements in mean Hct (from
30.1% to 35.9%, P <0.001) and mean Hb
(from 10.2 g/dL to 12.1 g/dL, P <0.001).
Serum iron and iron saturation levels
improved as well. Twenty-four of the 26
patients experienced functional improve-
ment, with the mean NYHA functional
class decreasing from 3.7 prior to treat-
ment to 2.7 at the end of the study.
Patients also showed improved renal
function and decreased use of oral and
intravenous furosemide. Furthermore,
patients required fewer hospitalizations,
with an overall decline in hospitalizations
of 91% when compared to a similar time
period prior to study treatment.
In a second controlled but unblinded
study by these investigators, correction
of anemia with epoetin and intravenous
iron was compared to no anemia cor-
rection in 32 patients with moderate to
severe heart failure. In this study, cor-
rection of anemia to a Hb level of ≥12.5
mg/dL improved NYHA functional clas-
sification (mean increase of 42%),
reduced the need for oral and intra-
Anemia: A Hidden Epidemic
venous diuretics (91% and 51%, respec-
tively), and reduced the number of hos-
pitalization days by 79%. In contrast,
patients with untreated anemia showed
a decline in NYHA functional class
(mean decrease of 11%), increased
need for oral and intravenous diuretics
(mean increases of 29% and 28%,
respectively), and a 58% increase in
hospitalizations.20
Preliminary data in a pilot study of
patients with severe heart failure by
Mancini and colleagues demonstrated
that correction of anemia with epoetin
improved exercise capacity.39 This con-
trolled study involved 22 anemic
patients (mean baseline Hb of 10.9
g/dL) with severe left ventricular dys-
function (LVEF22 ± 4%) who were ran-
domized in a 2:1 fashion to either no
treatment or 5,000 to 10,000 units of
epoetin given subcutaneously per week
for 3 months. From baseline to the end
of study, these investigators demonstrat-
ed a significant improvement (P <0.05)
in maximal oxygen consumption during
exercise treadmill testing in the 14
patients who received erythropoietin
therapy. In contrast, no change was
found in maximal oxygen consumption
during a similar period of follow-up of
eight control patients. Favorable trends
were also noted in the treated group on
6-minute-walk testing and assessment of
quality of life by the Minnesota Living
with Heart Failure questionnaire. The
augmentation of exercise performance
in the patients treated with erythropoi-
etin was associated with a change in Hb
from 10.9 g/dL at baseline to 14.3 g/dL
after 3 months of therapy. In contrast,
Hb concentration was stable in the con-
trol group.
III. Anemia & Cardiovascular Disease
AMI
The data of Wu and colleagues sug-
gest that transfusion, presumably by
improving anemia, may be beneficial in
elderly patients hospitalized for AMI.28
Although the study was retrospective
and the results must be interpreted
with caution, the findings of benefit
from transfusion were striking.
25
Transfusion was associated with a
reduced mortality rate in patients with
Hct <30% and may be effective even in
patients with Hct as high as 33%.
Additional studies are needed, but
these findings provide evidence that
treatment of anemia may be an impor-
tant component of therapy for AMI in
certain patients.
26 Anemia: A Hidden Epidemic
References
 C A R D I O VA S C U L A R D I S E A S E
References

1. Amsterdam PB. Comprehensive Cardiovascular Medicine. Philadelphia, PA: Lippincott-Raven;

1998.
2. Levin A, Thompson CR, Ethier J, et al. Left ventricular mass index increase in early renal dis-
ease: impact of decline in hemoglobin. Am J Kidney Dis. 1999;34:125-134.
3. Foley RN, Parfrey PS, Harnett JD, et al. The impact of anemia on cardiomyopathy, morbidity,
and mortality in end-stage renal disease. Am J Kidney Dis. 1996;28:53-61.
4. Lee GR, Foerster J, Lukens J, et al. Wintrobe’s Clinical Hematology. Baltimore, MD: Williams
and Wilkins; 1995.
5. London G. Pathophysiology of cardiovascular damage in the early renal population. Nephrol
Dial Transplant. 2001;16(suppl 2):3-6.
6. Eckardt KU. Anaemia in end-stage renal disease: pathophysiological considerations. Nephrol
Dial Transplant. 2001;16(suppl 7):2-8.
7. Duke M, Abelmann WH. The hemodynamic response to chronic anemia. Circulation.
1969;39:503-515.
8. Anand IS, Chandrashekhar Y, Ferrari R, et al. Pathogenesis of oedema in chronic severe
anaemia: studies of body water and sodium, renal function, haemodynamic variables, and
plasma hormones. Br Heart J. 1993;70:357-362.
9. Patterson JH, Adams KF, Jr. Pathophysiology of heart failure: changing perceptions.
Pharmacotherapy. 1996;16(pt 2):27S-36S.
10. Adams KF, Jr. Which beta-blocker for heart failure? Am Heart J. 2001;141:884-888.
11. Levin A, Singer J, Thompson CR, et al. Prevalent left ventricular hypertrophy in the predialysis
population: identifying opportunities for intervention. Am J Kidney Dis. 1996;27:347-354.
12. London GM, Marchais SJ, Guerin AP, et al. Cardiovascular function in hemodialysis patients.
Adv Nephrol Necker Hosp. 1991;20:249-273.
13. Collins AJ, Li S, St Peter W, et al. Death, hospitalization, and economic associations among
incident hemodialysis patients with hematocrit values of 36 to 39%. J Am Soc Nephrol.
2001;12:2465-2473.
14. Braunwald E, Zipes EP, Libby P. Heart Disease. A Textbook of Cardiovascular Medicine.
Philadelphia, PA: W B Saunders Co; 2001.
15. Packer M, Cohn JN. Consensus recommendation for the management of chronic heart fail-
ure. Am J Cardiol. 1999;83:1A-38A.
16. Volpe M, Tritto C, Testa U, et al. Blood levels of erythropoietin in congestive heart failure and
correlation with clinical, hemodynamic, and hormonal profiles. Am J Cardiol. 1994;74:468-
473.
17. Maeda K, Tanaka Y, Tsukano Y, et al. Multivariate analysis using a linear discriminant function
for predicting the prognosis of congestive heart failure. Jpn Circ J. 1982;46:137-142.
18. Haber HL, Leavy JA, Kessler PD, et al. The erythrocyte sedimentation rate in congestive
heart failure. N Engl J Med. 1991;324:353-358.
19. Jensen JD, Eiskjaer H, Bagger JP, et al. Elevated level of erythropoietin in congestive heart
failure: relationship to renal perfusion and plasma renin. J Intern Med. 1993;233:125-130.
20. Silverberg DS, Wexler D, Blum M, et al. The use of subcutaneous erythropoietin and intra-
venous iron for the treatment of the anemia of severe, resistant congestive heart failure
improves cardiac and renal function and functional cardiac class, and markedly reduces
hospitalizations. J Am Coll Cardiol. 2000;35:1737-1744.
21. Abboud C, Lichtman MA. Williams Hematology. 5th ed. New York, NY: McGraw Hill; 1995.
 C A R D I O VA S C U L A R D I S E A S E
References

22. Iversen PO, Woldbaek PR, Tonnessen T, et al. Decreased hematopoiesis in bone marrow of
mice with congestive heart failure. Am J Physiol Regul Integr Comp Physiol. 2002;282:R166-
R172.
23. Chatterjee B, Nydegger UE, Mohacsi P. Serum erythropoietin in heart failure patients treated
with ACE-inhibitors or AT(1) antagonists. Eur J Heart Fail. 2000;2:393-398.
24. Salahudeen AK, Oliver B, Bower JD, et al. Increase in plasma esterified F2-isoprostanes fol-
lowing intravenous iron infusion in patients on hemodialysis. Kidney Int. 2001;60:1525-1531.
25. Cruz DN, Perazella MA, Abu-Alfa AK, et al. Angiotensin-converting enzyme inhibitor therapy
in chronic hemodialysis patients: any evidence of erythropoietin resistance? Am J Kidney
Dis. 1996;28:535-540.
26. Al-Ahmad A, Rand WM, Manjunath G, et al. Reduced kidney function and anemia as risk fac-
tors for mortality in patients with left ventricular dysfunction. J Am Coll Cardiol. 2001;38:955-
962.
27. Fonarow GC, Horwich TB, Hamilton MA, et al. Anemia is associated with worse symptoms,
greater impairment in functional capacity, and a significant increase in mortality in patients
with advanced heart failure. J Am Coll Cardiol. 2002;39:184A.
28. Wu WC, Rathore SS, Wang Y, et al. Blood transfusion in elderly patients with acute myocar-
dial infarction. N Engl J Med. 2001;345:1230-1236.
29. Goodnough LT, Bach RG. Anemia, transfusion, and mortality. N Engl J Med. 2001;345:1272-
1274.
30. Ludwig H, Fritz E. Anemia in cancer patients. Semin Oncol. 1998;25(suppl 7):2-6.
31. London GM, Pannier B, Guerin AP, et al. Alterations of left ventricular hypertrophy in and sur-
vival of patients receiving hemodialysis: follow-up of an interventional study. J Am Soc
Nephrol. 2001;12:2759-2767.
32. Hayashi T, Suzuki A, Shoji T, et al. Cardiovascular effect of normalizing the hematocrit level
during erythropoietin therapy in predialysis patients with chronic renal failure. Am J Kidney
Dis. 2000;35:250-256.
33. Lopez-Gomez JM. Effects of partial correction of anemia on left ventricular structure and
function: Proc American Society of Nephrology 33rd annual meeting; 2000.
34. Silberberg J, Racine N, Barre P, et al. Regression of left ventricular hypertrophy in dialysis
patients following correction of anemia with recombinant human erythropoietin. Can J
Cardiol. 1990;6:1-4.
35. Zehnder C, Zuber M, Sulzer M, et al. Influence of long-term amelioration of anemia and
blood pressure control on left ventricular hypertrophy in hemodialyzed patients. Nephron.
1992;61:21-25.
36. Pascual J, Teruel JL, Moya JL, et al. Regression of left ventricular hypertrophy after partial
correction of anemia with erythropoietin in patients on hemodialysis: a prospective study.
Clin Nephrol. 1991;35:280-287.
37. Wizemann V, Kaufmann J, Kramer W. Effect of erythropoietin on ischemia tolerance in ane-
mic hemodialysis patients with confirmed coronary artery disease. Nephron. 1992;62:161-
165.
38. Silverberg DS, Wexler D, Sheps D, et al. The effect of correction of mild anemia in severe,
resistant congestive heart failure using subcutaneous erythropoietin and intravenous iron: a
randomized controlled study. J Am Coll Cardiol. 2001;37:1775-1780.
39. Mancini D, Katz S, LaManca J. Erythropoietin improves exercise capacity in patients with
heart failure. Vol 104(suppl II): Circulation; 2001.