Causes of Fatigue in Patients with Heart Failure

Donna Mancini, MD

Columbia University

New York, NY

Symptoms of CHF

• Fatigue

• Dyspnea

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)

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

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

Elements of Fatigue

• Psychological: Mental Weariness

• Physiologic: Physical inability– Central– Peripheral

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

Isokinetic Strength Testing• Maximum Voluntary

Contraction• Fatigue Index

– Duration of a sustained contraction

– Endurance: multiple repetitions

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

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

Cardiac Output Response

Weber, Circ 1982;65:1215

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)

Muscle HypothesisMuscle as a Sensory Organ

LV dysfunction

Decreased Perfusion Increased Cytokines Decreased Activity

ExerciseMuscleAtrophic

DeconditionedMetabolically abnl

Afferents

Fatigue Breathlessness

Hypoxia

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

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

Mancini, Circ 1992;86:909

NL CHF

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

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

Mancini, Circ 1992;86:909

Enzyme ChangesFiber Type Changes

Mancini, Circ 1992;86:909

Hambrecht JACC 1997;29:1067

Hambrecht, JACC 1999;33:174

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

Mancini Circ 1994;90:500

Kao W, AJC 1995;76:606

PCrConcentration

ATP use &production

ATP use stopsAccelerated production continues

WORK

Start Stop

Mancini Circ 1992;85:1364

Mancini Circ 1992;85:1364

Recovery time provides an index of oxidative metabolismIndependent of muscle mass

CHFNL

Mancini Circ 1994;90:500

Reduced oxidative metabolismDespite similar oxygenation level

Chati, AHJ 1996;131:560

Coats, Circ 1992;85:2119

Mancini Circ 1992;86:909

Mancini Circ 1992;86:909

Mancini Circ 1992;86:909

Low frequency fatigue does not occur

Mancini Circ 1992;86:909TTI= (Pdi/Pdi max) * (Ti/Ttot)

Figure 1Graphic

Nl

HF

Tikunov Circ 1997;95

Tikunov Circ 1997;95

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

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

Hormonal Changes

• Sympathetic Activation

• Renin Angiotensin Activation

• GH Resistance

• Insulin Resistance

• Increased cytokines

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

Nutrient Use During Exercise

36

14 8

37

50 62

2736 30

0%

25%

50%

75%

100%

40 180 240

Exercise Duration (min)

GlucoseFFALocal

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

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

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

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

0

10

20

30

40

NORMAL CHF

BaselineDepletedSlowed

p=NS

Peak VO2

(N=7) (N=13)

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

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.

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

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%

Hemoglobin in Epo Group

8

12

16

Pre-EPO Post-EPO

*P<0.001

1.8

-0.5

-3

0

3

VO

2 (m

l/k

g/m

in)

Control EPO

Change in Peak VO2

P<0.02

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)

Downward SpiralDecreased COSympathetic Stimulation

Decrease SM Blood FlowVasoconstriction

InactivityCytokine Activation Muscle wasting

DeconditioningAnemia

InactivityAnorexiaDepression

More Muscle wastingDecondtioningCachexia

FATIGUE