High Blood, Low Blood, Bad Blood, and Electric Lights: Geriatrics in the Inner City

1
Anemia and Heart Failure Cognition, Affect, and
Functional Status
Susan G. Nayfield, M.D., M.Sc. Geriatrics and
Clinical Gerontology Program National Institute
on Aging September 6, 2007
2
Anemia is Common in the ElderlyGuralnik et al,
Blood. 20041042263-2268
World Health Organization definition Hgb lt
12g/dl ?and Hgb lt 13 g/dl ?
3
Medical Correlates of Anemia in the Elderly

• Reduced survival, increased risk of death
• Frailty, increased risk of and more rapid
  functional deterioration
• Increased risk of CHF and death from acute
  coronary events
• Increased risk of cognitive impairment and
  dementia

Caveat Anemia is a frequent flyer but does not
usually travel alone!
4
Anemia and Executive Function
Chaves et al. J Amer Geriatr Soc 541429-35, 2006

• Womens Health and Aging Study II
• Community-dwelling women ages 70-80 years
• High physical function, MMSE 24 or greater
• Hgb 10-12 g/dl (mild anemia)
• Trail Making Test (TMT)
• Increased likelihood of performing in worst
  tertile
• TMT-B (mental flexibility and psychomotor
  processing speed) OR 5.2, 95 CI 1.3-20.5
• TMT-A (motor speed and visuospatial ability) OR
  4.8, 95 CI 1.5-15.6
• TMT-B TMT A (less influenced by motor agility)
  OR 4.2. 95 CI 1.0-17.2
• Unanswered questions
• Causal or modulated by comorbid conditions?
• Mediated by etiology of anemia?

5
Anemia and Physical Performance

• EPESE Study (Am J Med 115104, 2003)
• Anemic patients performed worse on baseline
  physical performance battery
• Degree of anemia correlated with decline in
  performance for both ? and ?
• Decline similar for microcytic, normocytic, or
  macrocytic anemias
• Womens Health and Aging Study (J Am Geriatr Soc
  501257, 2002)
• Prevalent mobility difficulty not constant within
  WHO normal hemoglobin range
• Trend in improvement of performance-based scores
  of lower extremity function (SPS) with increasing
  hemoglobin
• InCHIANTI Study (J Am Geriatr Soc 52719, 2004)
• Anemia prevalence 11
• Anemia associated with
• Increase in disability (ADLs and IADLs)
• Poorer performance on SPPB
• Poorer knee extensor and hand grip strength

6
Anemia and Depression
Onder et al. J Gerontol Med Sci 60A1168-72, 2005

• InCHIANTI Study
• Community-dwelling men (44) and women (56)
• Mean age 75 years
• Anemia by WHO criteria (? lt 13 g/dl ? lt 12 g/dl)
• CES-D gt 16 considered depressed
• Increased likelihood of depression with anemia
• Depression in 32 of study participants
• Anemia in 10 of study participants
• Anemia in 15 with depression and 8 without
  depression
• Depression associated with increased risk of
  anemia (OR1.93 95 CI 1.19-3.13)
• Risk of anemia increased with increasing CES-D
  score

7
Anemia and Depression
Onder et al. J Gerontol Med Sci 60A1168-72, 2005
8
Etiology of Anemia in the ElderlyGuralnik et al,
Blood. 20041042263-2268
9
Iron

• Dietary sources Green vegetables, meat
• Hepcidin (liver) regulates intestinal absorption
  and storage/release from bone marrow
• Erythropoeitin (kidney) regulates RBC production
  in bone marrow
• Iron complexes with protein chains
• Hemoglobin in RBC cytoplasm (67)
• Ferritin and hemosiderin (27)
• Myoglobin in cardiac and skeletal muscle (4)
• Cytochromes and iron-containing enzymes (lt1)
• Oxygen-carrying mechanism in RBC
• In iron deficiency anemia, RBCs are small and
  pale (microcytic, hypochromic)

10
Figure 2. Hepcidin synthesis in the liver and its
effects on iron metabolism.
(Ganz, 2003).
11
Functional Outcomes and Severity of Iron
Deficiency
Beard JL. J Nutr 131568S-580S, 2001
12
Iron Deficiency and Cognition

• Iron in normal brain development during gestation
• Neurotransmitter effects (dopamine)
• Hippocampus development (recognition memory)
• Myelination
• Iron deficiency anemia in infants
• Impaired cognitive, motor, socio-emotional and
  neurophysiologic development
• Partially mitigated by early intervention (?)
• School aged children (late effects)
• Lower language and fine motor skills
• Attention and learning disabilities
• Confounded by SES
• Iron and cognitive functioning in young women

13
Iron and Cognitive Function in Young Women
Murray-Kolb LE and Beard JL. Amer J Clin Nutr
85778-87, 2007

• Blinded RCT in ? ages 18-35 years
• Normal (42)
• Iron deficient (decreased iron stores) (73)
• Iron deficiency anemia (34)
• Baseline
• Normal performed cognitive tests more accurately
  and faster than IDA
• Iron deficient subjects were intermediate
• Following treatment
• ? ferritin ? 5-7 fold improvement in cognitive
  test
• ? hemoglobin ? improved time for completion

14
Vitamin B12 and Folate
Vitamin B12
Folate

• Dietary source Animal products
• Major metabolites methylmalonic acid
• Necessary for methyl transfer and DNA synthesis
• Megaloblastic, macrocytic anemia
• Deficiency also associated with
• Dementia
• Depression, acute psychosis (megaloblastic
  madness)
• ? Risk of stroke (homocysteine)
• Subacute combined degeneration of spinal cord
• Motor-sensory peripheral neuropathy
• Autonomic neuropathy

• Dietary source Vegetables and fortified grain
  products
• Major metabolite homocysteine
• Interacts with Vitamin B12 in methyl transfer and
  DNA synthesis
• Megaloblastic, macrocytic anemia
• Deficiency during pregnancy associated with
  neural tube defects
• Deficiency also associated with neurological
  manifeststions similar to those of Vitmin B12
  deficiency.

15
? DNA synthesis
THF Tetrahydrofolate
Vitamin B12 absorption, transport in the
circulation, and function within the cell.
Hvas and Nexo. Haematologica 2006911506-1512
16
Vitamin B12 and Depression
Penninx et al. Am J Psychiatry 157715-21, 2000

• Womens Health and Aging Study subset
• 700 physically disabled women, mean age 77 years
• MMSE 18 or higher
• Geriatric Depression Scale
• Serum B12, folate, methylmalonic acid,
  homocysteine
• Vitamin status
• B12 deficiency 17
• Folate deficiency 3
• Combined deficiencies 3
• Depression
• 32 depressed (GDS gt 10)
• 14 mild (GDS 10 - 13)
• 18 severe (GDS gt 14)

17
Vitamin B12 and Depression
Penninx et al. Am J Psychiatry 157715-21, 2000

• Depression
• MILD no association with B12 or folate
  deficiency
• SEVERE
• Strong association with B12 deficiency (OR 2)
• No association with folate deficiency
• Anemia more common in B12 deficient subjects
  (17) than in normal subjects (11) (p0.05)
• B12 deficient subjects more likely to have
  congestive heart failure (p0.02)
• No association between B12 deficiency and
  cognitive function on MMSE
• Anemia not associated with depression status

18
Vitamin B12, Folate, Homocysteine and Alzheimers
DiseaseThe Homocysteine Hypothesis of Dementia

• Framingham Study (8 year follow-up) Elevated
  serum homocysteine associated with a 2-fold
  increased risk of dementia
• Rotterdam Scan Study Elevated homocysteine
  associated with
• Radiographic findings of white matter lesions,
  silent infarcts, atrophy of cerebral cortex and
  hippocampus
• Cognitive impairment
• Literature review Inadequate evidence of effect
  of B12 or folate supplementation on cognitive
  function in persons with normal or impaired
  cognition

19
A Controlled Trial of Homocysteine Lowering and
Cognitive Performance
McMahon et al. N Engl J Med 3542764-72, 2006
20
A Controlled Trial of Homocysteine Lowering and
Cognitive Performance
McMahon et al. N Engl J Med 3542764-72, 2006
21
Vitamin B12 and Folate Status in Relationship to
Anemia, Macrocytosis, and Cognitive Impairment in
an Age of Dietary Folate Supplementation
Morris et al, Am J Clin Nutr 200785193-200

• NHANES II (1999-2002) participants ages gt 60
  years
• Anemia WHO criteria (? Hgb lt12 g/dL ? lt13 g/dL)
• Macrocytosis MCV gt 99fL
• Cognitive Function Digit Symbol-Coding subtest
  of Wechsler Adult Intelligence Scale III
• Vitamin B12 classified as low by conventional
  standards
• Folate classified as high if above 80th
  percentile for seniors in study

22
Vitamin B12 and Folate Status in Relationship to
Anemia, Macrocytosis, and Cognitive Impairment

• Inverse relationship between macrocytosis and
  serum ferritin (measure of iron stores)
• For normal vitamin B12, protective effect of high
  folate for cognitive impairment and anemia
• For low vitamin B12 status
• Increased prevalence of anemia and cognitive
  impairment regardless of folate status
• Worst combination low vitamin B12 and high
  folate 5-fold increase in both anemia and
  cognitive impairment compared to normal B12 and
  folate

23

Study Results
OUTCOME B12 Status Folate Status Subjects with Outcome OR (95 CI)
Anemia Normal Normal 913 3.5 1.0
Anemia Normal High 198 2.9 0.6 (0.2, 2.2)
Anemia Low Normal 297 6.9 2.0 (1.1, 3.5)
Anemia Low High 49 15 4.9 (2.3, ,10.6)
Cognitive Impairment Normal Normal 826 18 1.0
Cognitive Impairment Normal High 180 11 0.4 (0.2, 0.9)
Cognitive Impairment Low Normal 253 25 1.7 (1.01, 2.9)
Cognitive Impairment Low High 42 45 5.0 (2.7, 9.5)
24
Heart FailureKannel and Bellinger. Am Heart J
1991 121951
Incidence and prevalence of heart failure by age
and sex. 30-year follow-up from the Framingham
study.
25
Heart Failure Cognition, Affect and Functional
Status

• Cognition
• Cognitive dysfunction in 35 to gt50 of CHF
  patients
• Shared risk factors for cerebrovascular disease
• Decreased CNS perfusion
• Associated with 5x increase in mortality and 6x
  increase in ADL dependence
• Depression
• Prevalence 13 - 77, depending on definition and
  population
• Graded, independent risk factor for
• Poor treatment compliance
• Increased hospital admissions and healthcare
  costs
• Mortality
• CBT and SSRIs are treatment of choice
• Functional Status
• Classification of heart failure based on symptoms
  with exertion

26
Heart Failure and Physical FunctionNYHA
Classification
Class Patient Symptoms
Class I (Mild) No limitation of physical activity. Ordinary physical activity does not cause fatigue, palpitation, or dyspnea.
Class II (Mild) Slight limitation of physical activity. Comfortable at rest, but normal activity causes fatigue, palpitation, or dyspnea.
Class III (Moderate) Marked limitation of physical activity. Comfortable at rest, but less than normal activity causes fatigue, palpitation, or dyspnea.
Class IV (Severe) Unable to carry out any physical activity without discomfort. Symptoms of cardiac insufficiency at rest, increased by activity.
27
Anemia and Heart Failure

• Prevalence of anemia increases with severity of
  heart failure
• 5-20 of patients newly-diagnosed with heart
  failure
• Up to 80 of patients with NYHA Class IV heart
  failure
• Overall prevalence about 30-35
• Excess morbidity and mortality
• mortality approximately 13 for each 1 g/dL
  decrease in Hgb
• Decreased survival noted at relatively mild
  anemia
• (? lt11.6 g/dL, ? lt12.6 g/dL)
• Correction of anemia may lead to reduction in
  morbidity, hospitalization rates, and mortality

28
Causes of Anemia in Heart Failure

• Congestive heart failure mechanisms
• Hemodilution
• Inflammation associated with heart disease
• Reduced nutrient uptake due to small bowel edema
• Drugs used to treat heart failure
• Comorbid conditions associated with anemia,
  particularly CKD and diabetes
• EPO suppression
• Inflammation associated with CKD, diabetes
• Combinations of the above (multifactorial)

29
Mechanisms of Anemia Related to Heart Failure
Tang and Katz. Circulation 20061132454-2461
30
Anemia and Survival in Heart FailureKosiborod et
al. Am J Med 2003114112-119
31
Anemia is an Independent Predictor of Mortality
in Heart Failure Regardless of Systolic Function
Felker et al, Am Heart J 2006151457-62
32
Impact of Anemia and Heart Failure on Risk of ADL
Disability
Maraldi et al, J Cardiac Fail 200612533-539
33
Erythropoietin (EPO)

• Glycoprotein hormone adjusts RBC production to
  meet tissue oxygen demands
• Produced by kidney in response to oxygen sensor
  mechanism
• EPO receptors in multiple tissues, including
  vascular smooth muscle and cardiac muscle
• EPO treatment limits myocardial infarct size in
  rodent models using coronary artery ligation
• EPO paracrine system in CNS
• EPOR in hippocampus and cerebral cortex
• IEPO infusion in lateral ventricles of hamsters
  prevents ischemia-related learning disability and
  limits infarct size in HTN-prone rats

34

Erythropoietin and Iron in the Treatment of
Anemia in Heart Failure

• rHuEPO used in therapy of anemia associated with
  decreased EPO levels CKD, cancer, AIDS
• ?EPO in anemia/heart failure inappropriate for
  level of Hgb
• EPO-unresponsive or partially responsive patients
  may converted with administration of IV iron
  despite normal iron stores
• Unavailability of stored iron mediated by
  hepcidin (ACD/ACI)
• Potential for iatrogenic iron overload and tissue
  deposition
• Hypertension develops or worsens in 20-30 of CKD
  patients on EPO
• ? Hgb associated with ? thrombotic events in CKD

35
Treatment of Anemia in Heart Failure
Silverberg et al. Am Coll Cardiol
2000351737-1744
Open-label study of 26 patients with anemia and
heart failure treated with rHuEPO and intravenous
iron to achieve a hemoglobin of 12 g/dl.
Duration of therapy 4-15 months (mean 7 months).
36
Treatment of Anemia in Heart Failure
Silverberg et al. Am Coll Cardiol
2000351737-1744
37
Treatment of Anemia in Heart Failure
Mancini et al. Circulation 2003107294-299
Randomized controlled study of 26 anemic patients
with NYHA Class III-IV heart failure treated with
EPO vs placebo for up to 3 months. Targeted
increase in Hct gt45.
PNS
10.91.1
11.51.3
Plt0.001
110.6
14.31.2
38
Treatment of Anemia in Heart Failure
Mancini et al. Circulation 2003107294-299
39
Treatment of Anemia in Heart Failure
Palazzuoli et al. Am Heart J 20061521096.e9-15
Double blind RCT of 40 patients with anemia (Hgb
lt 11 g/dL) and moderate to severe heart failure
treated with rHuEPO and oral iron or placebo and
oral iron
40
Treatment of Anemia in Heart Failure
Palazzuoli et al. Am Heart J 20061521096.e9-15
EPO
Placebo
41
Treatment of Anemia and Change in Left
Ventricular Mass and Function
Jones et al. Int J Cardiol 2005100253-265
(Meta-analysis)
42
Reduction of Events with in Heart Failure (RED-HT)
Young et al. J Card Failure 200612 (Supp 1)S77

• Global, multicenter, randomized, double-blind,
  placebo-controlled Phase III clinical trial
• Goal to determine the impact of treatment of
  anemia with Darbepoeitin-a in patients with
  symptomatic left ventricular dysfunction
• Outcomes Morbidity and mortality
• Participants 3,400 patients with Hgb 9.0-12.0
  g/dL
• Intervention dose titrated to achieve Hgb
  13.0-14.5 g/dL
• Duration 3 years or when 1,450 participants have
  experienced a primary endpoint event

43
Summary

• Anemia alone may be associated with cognitive
  impairment, depression, and declining physical
  performance
• Obvious mechanism ? oxygen delivery to tissue
• For dietary deficiencies, nutrients as
  independent factors
• Role of Vitamin B12 and Folate in dementia is
  unproven
• Heart failure alone may be associated with
  cognitive impairment, depression, and declining
  physical performance
• Co-occurrence of heart failure and anemia
• Associated with increased morbidity and mortality
• Poor outcomes worsened by other comorbidity

44
Research Challenges

• For iron deficiency or unavailability (ACD/ACI)
• Is anemia really the culprit, or is iron the
  critical element?
• If iron is the critical element, can we target
  hepcidin in conditions associated with
  inflammation?
• For the B12, folate and homocysteine conundrum
• Life course approach?
• Pleotrophic effects (different tissues or points
  in life course?
• Public health impact?
• EPO /- iron in the treatment of anemia in CHF
• How much of the observed benefit in physiologic
  and physical function is due to
• Correction of anemia?
• Iron replacement?
• Direct tissue effects of EPO?

45
Research Challenges (2)

• EPO in CHF (continued)
• If EPO is the critical factor, can we induce EPO
  through alternate physiologic pathways?
• Does EPO within the CNS modulate mood and
  affect?
• Does EPO within the CNS modulate mood and affect?
  If so
• Where and how?
• Can we channel drug discovery technology to take
  advantage of this benefit?
• Clinical trials of treatment of anemia and/or
  heart failure
• Comprehensive measures of cognitive function
• Affect
• Functional outcomes

46
Is EPO Really Necessary or is Iron Sufficient?