causes of fatigue in patients with heart failure donna mancini, md columbia university new york, ny
TRANSCRIPT
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Causes of Fatigue in Patients with Heart Failure
Donna Mancini, MD
Columbia University
New York, NY
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Symptoms of CHF
• Fatigue
• Dyspnea
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Fatigue in HF• Impaired Cardiac Output Response with Skeletal
Muscle Hypoperfusion• Abnormal Vasodilation/Altered Endothelial Fn• Skeletal Muscle Dysfunction• Malnutrition/Cachexia• Cytokine Activation• Anemia• Depression• Sleep apnea• Medications (ß blockers; overdiuresis)
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Non-Cardiac CoMorbidities in Patients >65 yrs with CHF (n=122,630)
• Essential HT- 55%• HT w complications-11%• Diabetes-31%• COPD-26%• Other respiratory disorders-
11%• Asthma-5%• Ocular Disorders-24%• Hypercholesterolemia-21%
• Osteoarthritis-16%• Osteoporosis-5%• Alzheimer’s-9%• Depression-8%• Anxiety-3%• Chronic Renal Failure 7%• Renal Insufficiency-4%• PVD-16%• Thyroid 14%• Cerebrovascular Disease-3%
Braunstein, JACC 2003;42: 1793
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Padeletti, Sleep Medicine 2008;1132
• CHF associated with Central and ObstructiveSleep Apnea in up
to 40% of stable HF pts
• 28 of 29 patients admitted with acute decompensated CHF had SDB
• Patients with SDB have lower peak VO2 vs those without
• Interventions associated with increase in VO2 such as CRT are also associated with decrease in SDB
QuickTime™ and aTIFF (Uncompressed) decompressor
are needed to see this picture.
Cheyne Stokes- Central Sleep Apnea
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Elements of Fatigue
• Psychological: Mental Weariness
• Physiologic: Physical inability– Central– Peripheral
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Lung Heart Muscle
VO2= O2 delivery-O2 extractionVO2= CO * (A-VO2 difference)
O2 delivery: Cardiac Output Pulmonary Function Hemoglobin Concentration
O2 Extraction: Muscle Oxidative Capacity Vasodilatory Capacity
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Isokinetic Strength Testing• Maximum Voluntary
Contraction• Fatigue Index
– Duration of a sustained contraction
– Endurance: multiple repetitions
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Qualitative Assessments of Fatigue
• Ratings of Perceived Fatigue -Borg Scale– Scale of 6-20 corresponds to HR response to
exercise
• Quality of Life Questionnaires
• Visual Analogue Scales
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Decreased CO response
• Results in decreased skeletal muscle perfusion• Early Lactic acidosis• Fatigue
Peak Cardiac Output (L/min)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 150.0
7.4
14.8
22.2
29.6
37.0
y = 4.746119 + 1.089822 * x
r=0.64;p<0.0001
Lang Am J Cardiol 2007
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Cardiac Output Response
Weber, Circ 1982;65:1215
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Skeletal Muscle in CHF
• Morphological Changes (reduction in muscle mass)
• Histological Changes (shift in fiber types)
• Biochemical changes: shift from oxidative to glycolytic metabolism (31P MRS)
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Muscle HypothesisMuscle as a Sensory Organ
LV dysfunction
Decreased Perfusion Increased Cytokines Decreased Activity
ExerciseMuscleAtrophic
DeconditionedMetabolically abnl
Afferents
Fatigue Breathlessness
Hypoxia
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Anthropomorphic Assessement (n=62)
0
25
50
75
<5 (5-25) (25-50)
>50
Arm Muscle Circumference (% of standard)
Per
cen
t of
Pat
ien
ts
0
25
50
75
<5 (5-25) (25-50)
>50
Triceps Skin Fold (% of standard)
Per
cen
t of
Pat
ien
ts
Mancini Circ 1989;80:1338
Muscle Wasting
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DEXA Scanning in CHF
Controls (n=16)
Noncachetic (N=40)
Cachetic (n=18)
Total Fat (kg)
207 228 144*
Muscle (kg) 584 576 465*
Bone (kg) 3.1.4 3.1.3 2.6.2*
Anker AJC 99:83
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Mancini, Circ 1992;86:909
NL CHF
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Pathogenic Factors for Cardiac Cachexia
• Generalized Cellular Hypoxia• Decreased Caloric Intake
– Anorexia from gastric and hepatic congestion– Depression
• Increased Caloric Expenditure– Increased Work of Breathing– Increased Metabolic Rate
• Iatrogenic Factors– Salt and Water Restriction– Diuretics, Cardiac Glycosides– Therapeutic Removal of body fluids
Anasari, Progress in CV Disease 1987
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Histologic Changes
Type I and II Atrophy Type II b Type I oxidative enzymes mitochondria volume
ATPase stain @pH 4.6
NL CHF CHF
Mancini, Circ 1992;86:909
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Mancini, Circ 1992;86:909
Enzyme ChangesFiber Type Changes
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Mancini, Circ 1992;86:909
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Hambrecht JACC 1997;29:1067
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Hambrecht, JACC 1999;33:174
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Other Skeletal Muscle Changes
• Increased apoptosis (Vescovo JMoll CellCardiol 1998)
• Oxidation of myosin (Coirault Am J Physiol 2007)
• Hyperphosphorylation of the ryanodine receptor (Wehrens PNAS Medical Sciences 2005)
• Decrease in SERCA-2
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Mancini Circ 1994;90:500
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Kao W, AJC 1995;76:606
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PCrConcentration
ATP use &production
ATP use stopsAccelerated production continues
WORK
Start Stop
Mancini Circ 1992;85:1364
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Mancini Circ 1992;85:1364
Recovery time provides an index of oxidative metabolismIndependent of muscle mass
CHFNL
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Mancini Circ 1994;90:500
Reduced oxidative metabolismDespite similar oxygenation level
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Chati, AHJ 1996;131:560
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Coats, Circ 1992;85:2119
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Mancini Circ 1992;86:909
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Mancini Circ 1992;86:909
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Mancini Circ 1992;86:909
Low frequency fatigue does not occur
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Mancini Circ 1992;86:909TTI= (Pdi/Pdi max) * (Ti/Ttot)
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Figure 1Graphic
Nl
HF
Tikunov Circ 1997;95
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Tikunov Circ 1997;95
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Immune Activation in CHF
• Reduced peripheral blood flow results in local ischemia and macrophage activation leading to cytokine release and endothelial dysfunction
• Neurohormonal activation
• Catabolic state
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Plasma Hormones
Control (n=16)
Non-Cachetic
CHF (n=37)
Cachetic CHF
(n=16) TNF (pg/ml) 70.7 6.90.8 15.33.1†*
hGH (ng/ml) 1.10.4 0.90.3 3.81.6†*
Aldosterone (pmol/L)
27942 55277* 1039227†*
IGF-1 (nmol/L) 14811 1499 13713
* p<0.05 control vs cachetic; † control vs non cachetic
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Hormonal Changes
• Sympathetic Activation
• Renin Angiotensin Activation
• GH Resistance
• Insulin Resistance
• Increased cytokines
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Nutrition and Exercise
• Nutrition forms the basis for human performance
• Food nutrients provide energy and regulate physiologic processes
• Inadequate nutrition can hinder performance• Dietary Supplements may enhance
performance
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Nutrient Use During Exercise
36
14 8
37
50 62
2736 30
0%
25%
50%
75%
100%
40 180 240
Exercise Duration (min)
GlucoseFFALocal
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GLYCOGEN METABOLISM IN CHF
Accelerated glycogen utilization in animal heart failure models
Reduced or low normal glycogen concentration in human heart failure skeletal muscle biopsies
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POSSIBLE MECHANISMS OF ABNORMAL GLYCOGEN METABOLISM IN CHF:
Reduced delivery of substrates due to reduced muscle perfusion
Hormonal abnormalities -- elevated catecholamine levels
Intrinsic alteration of skeletal muscle metabolism with increased glycolytic activity
a. deconditioning
b. inhibition of free fatty acid metabolism
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PROTOCOLJACC1999;34:1807
Baseline:
Day 1: Exercise performed in fasting state 60% protein 40% fat drink provided Glycogen Depleted: Day 2: Exercise protocol repeated Slowed Glycogen Utilization: Day 8: 60% carbohydrate, 30% protein, 10% fat
drink provided Day 9: High fat breakfast (eggs, bacon, bagel) 3.5 hours later: Heparin 2000 U IV
4 hours later: exercise repeated
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Exercise Protocol
Maximal: incremental bicycle exercise using 25W workloads of 3 minutes duration with measurement of respiratory gases
Submaximal: 75% of peak workload until exhaustion
Supramaximal: 133% peak workload x 1 minute followed by 2 minutes rest;
repeated until subject is unable to complete a full min of exercise
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0
10
20
30
40
NORMAL CHF
BaselineDepletedSlowed
p=NS
Peak VO2
(N=7) (N=13)
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Submaximal Exercise Duration
0
10
20
30
NORMAL CHF
Exe
rcis
e D
ura
tio
n (
min
)
BaselineDepletedSlowed
*
*
p<0.05 within group
Glycogen Depletion: -57 vs -12% Nl vs HFSlowed Glycogen: 18 vs 65% Nl vs HF
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Anemia Is Common
in Heart Failure Patients
00 55 1515 2020 3030 4040 50504545
% of Heart Failure Patients With Anemia
1010 2525 3535
16%16%Tang (N=2009)Tang (N=2009)11
Anker, ELITE (N=3044Anker, ELITE (N=3044)217%17%
Ezekowitz, ICcodes(N=12,065)317%17%
Mozaffarian, PRAISE (N=1130)4 20%20%
22%22%Al-Ahmad, SOLVD (N=6563)5
28%28%Herzog, Medicare ICD (N=152,584)6
30%30%Horwich, UCLA CM clinic (N=1061)7
48%48%Kosiborod, Medicare (N=2281)8
1. Tang WHW, et al. ACC 2003. 2. Anker SD, et al. Circulation. 2002;106(suppl II):472.
Abstract 2335. 3. Ezekowitz JA, et al. Circulation. 2003;107:223-225. 4. Mozaffarian D, et al. J Am Coll Cardiol. 2003;41:1933-1939.
5. Al-Ahmad A, et al. J Am Coll Cardiol. 2001;38:955-62. 6. Herzog CA, et al. J Card Fail. 2002;8(suppl):S63.
Abstract 228. 7. Horwich TB, et al. J Am Coll Cardiol. 2002;39:1780-1786. 8. Kosiborod M, et al. Am J Med. 2003;114:112-119.
Prevalence varies with age, patient population, and definition of anemia.
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Potential Mechanisms for Enhancing Exercise Capacity
• Increase Hemoglobin and thus increase oxygen carrying capacity
• Reduce oxidative stress and improve vasodilatory capacity
• Increase rate of Oxygen delivery
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ProtocolMancini Circ 2003;107
• Randomized single blind prospective study in 27 HF patients
• 2:1 randomization – erythropoietin 5000-10,000 U SQ TIW +
ferrous gluconate 325 mg daily and folate 1 mg daily
– placebo injection of ‘Depot Epo’ (1cc normal saline)
– 3 month study or until Hct >45%
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Hemoglobin in Epo Group
8
12
16
Pre-EPO Post-EPO
*P<0.001
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1.8
-0.5
-3
0
3
VO
2 (m
l/k
g/m
in)
Control EPO
Change in Peak VO2
P<0.02
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Change in MLHFQ
10.0
-9.8-16
0
16
Un
its
Control Epo
*P<0.03
*P<0.016 min Walk
128
-108-150
0
150
Dis
tance (f
t)
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Downward SpiralDecreased COSympathetic Stimulation
Decrease SM Blood FlowVasoconstriction
InactivityCytokine Activation Muscle wasting
DeconditioningAnemia
InactivityAnorexiaDepression
More Muscle wastingDecondtioningCachexia
FATIGUE