1. Causes of Fatigue in Patients with Heart Failure
Donna Mancini, MD
Columbia University
New York, NY

2. Symptoms of CHF
Fatigue
Dyspnea

3. 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)

4. 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

5. 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
Cheyne Stokes- Central Sleep Apnea
Padeletti, Sleep Medicine 2008;1132

6. Elements of Fatigue Psychological: Mental Weariness
Physiologic: Physical inability
Central
Peripheral

7. VO2= O2 delivery-O2 extraction VO2= CO * (A-VO2 difference)
Muscle
Lung
Heart
VO2= O2 delivery-O2 extraction
VO2= CO * (A-VO2 difference)
O2 delivery:
Cardiac Output
Pulmonary Function
Hemoglobin Concentration
O2 Extraction:
Muscle Oxidative Capacity
Vasodilatory Capacity

8. Isokinetic Strength Testing
Maximum Voluntary Contraction
Fatigue Index
Duration of a sustained contraction
Endurance: multiple repetitions
Leg muscle strength and endurance were measured using an isokinetic dynometer (the Cybex system). The resistance of the lever arm is automatically adjusted to the dynamic tension produced by the muscle throughout its range of motion. The device records torque during muscle contraction at a selected angular velocity while correcting for the gravity contribution.
The dominant leg was tested. 5 maximal knee extensions and flexions were performed at 60 and 120 degrees.
The patient then performed 25 rapid contractions at the 120 speed. The fatigue ratio was defined as the average of the last 3 repetitions over the first 3.

9. 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

10. Decreased CO response Results in decreased skeletal muscle perfusion
Early Lactic acidosis
Fatigue
r=0.64;p<0.0001
Lang Am J Cardiol 2007

11. Cardiac Output Response
Weber, Circ 1982;65:1215

12. 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)

13. Muscle Hypothesis Muscle as a Sensory Organ
Atrophic
Deconditioned
Metabolically abnl
Hypoxia
Exercise
Returning now to the original muscle hypothesis:
Briefly, ergoreceptors are nerve muscle afferents which are sensitive to skeletal muscle work. Ergorecptor overactivation has been shown in patients with congestive heart failure. Continued activation of these receptors leads to the sensation of dyspnea and fatigue. We have shown that by selectively reconditioning the muscles of the lower extremities, the magnitude of dyspnea experienced is significantly reduced. This was achieved without changes in cardiac function or respiratory muscle strength. Thus by improving muscle function alone, easily achieved through rehab, one can improve symtoms though not necessarily change outcome.
Afferents
Breathlessness
Fatigue

14. Anthropomorphic Assessement (n=62)
Muscle Wasting
Anthropomorphic Assessement (n=62)
Mancini Circ 1989;80:1338

15. DEXA Scanning in CHF
Anker AJC 99:83

16. NL
CHF
Mancini, Circ 1992;86:909

17. 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

18. Histologic Changes NL CHF CHF ATPase stain @pH 4.6
Type I and II Atrophy
 Type II b
 Type I
 oxidative enzymes
 mitochondria volume NL
CHF
CHF
ATPase 4.6
Mancini, Circ 1992;86:909

19. Fiber Type Changes
Enzyme Changes
Mancini, Circ 1992;86:909

20. Mancini, Circ 1992;86:909

21. Hambrecht JACC 1997;29:1067

22. Hambrecht, JACC 1999;33:174

23. 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

24. Mancini Circ 1994;90:500

26. Kao W, AJC 1995;76:606

27. ATP use &
production
ATP use stops
Accelerated production continues
WORK
Stop
Start
PCr
Concentration
Mancini Circ 1992;85:1364

28. CHF NL
Recovery time provides an index of oxidative metabolism
Independent of muscle mass
Mancini Circ 1992;85:1364

29. Reduced oxidative metabolism
Despite similar oxygenation level
Mancini Circ 1994;90:500

30. Chati, AHJ 1996;131:560

31. Coats, Circ 1992;85:2119

32. Mancini Circ 1992;86:909

33. Mancini Circ 1992;86:909

34. Low frequency fatigue does not occur
Mancini Circ 1992;86:909

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

36. Nl
Figure 1
Graphic HF
Tikunov Circ 1997;95

37. Tikunov Circ 1997;95

38. 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

39. Plasma Hormones
* p<0.05 control vs cachetic; † control vs non cachetic

40. Hormonal Changes Sympathetic Activation Renin Angiotensin Activation
GH Resistance
Insulin Resistance
Increased cytokines

41. 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

42. Nutrient Use During Exercise

43. 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

44. 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

45. PROTOCOL JACC1999;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

46. 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

47. Peak VO2
p=NS
(N=13)
(N=7)

48. Submaximal Exercise Duration
p<0.05 within group * *
Glycogen Depletion: -57 vs -12% Nl vs HF
Slowed Glycogen: 18 vs 65% Nl vs HF

49. in Heart Failure Patients % of Heart Failure Patients With Anemia
Anemia Is Common
in Heart Failure Patients
16%
Tang (N=2009)1
Prevalence varies with age, patient population, and definition of anemia.
Anker, ELITE (N=3044)2
17%
Ezekowitz, ICcodes(N=12,065)3
17%
Mozaffarian, PRAISE (N=1130)4
20%
22%
Al-Ahmad, SOLVD (N=6563)5
28%
Herzog, Medicare ICD (N=152,584)6
30%
Horwich, UCLA CM clinic (N=1061)7
Key Point: The presence of anemia compounds the mortality risk of other pathologic conditions, such as chronic kidney disease and heart failure.
The authors analyzed claims records of 1.2 million patients in the 5% General Medicare Database identified in a 2-year ( ) entry cohort. The impact of independent predictors of mortality was examined in a Cox regression model. The study population was 39% male and 61% female; 89% white, 7% black, and 3% other races; with 29% between ages 65 and 69, 28% between 70 and 74, 21% between 71 and 79, and 23% aged 80 and older.
The authors concluded that, in Medicare patients, chronic kidney disease and anemia independently confer a 2-fold increased mortality risk and heart failure a nearly 3-fold increased mortality risk.
48%
Kosiborod, Medicare (N=2281)8 5 10 15 20 25 30 35 40 45 50
% of Heart Failure Patients With Anemia
5. Al-Ahmad A, et al. J Am Coll Cardiol. 2001;38:
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:
8. Kosiborod M, et al. Am J Med. 2003;114:
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:
4. Mozaffarian D, et al. J Am Coll Cardiol. 2003;41:
Tang WHW, Miller H, Partin M, Harris CM, Young JB. Anemia in heart failure: a single-center experience. Presented at the 52nd Annual Scientific Session of the American College of Cardiology; March 30-April 2, 2003; Chicago, Ill.
Anker SD, Sharma R, Francis D, et al. Patients with chronic heart failure (CHF) in the ELITE II trial. Circulation. 2002;106(suppl): 472. Abstract 2335.
Ezekowitz JA, McAlister FA, Armstrong PW. Anemia is common in heart failure and is associated with poor outcomes: insights from a cohort of patients with new-onset heart failure. Circulation. 2003;107:
Mozaffarian D, Nye R, Levy WC. Anemia predicts mortality in severe heart failure: the prospective randomized amlodipine survival evaluation (PRAISE). J Am Coll Cardiol. 2003;41:
Al-Ahmad A, Rand WM, Manjunath G, et al. Reduced kidney function and anemia as risk factors for mortality in patients with left ventricular dysfunction. J Am Coll Cardiol. 2001;38:
Herzog CA, Li S, Collins AJ. The impact of congestive heart failure (CHF), chronic kidney disease (CKD), and anemia on survival in the Medicare population. J Card Fail. 2002;8(suppl):S63. Abstract 226.
Horwich TB, Fonarow GC, Hamilton MA, MacLellan WR, Borenstein J. 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:
Kosiborod M, Smith GL, Radford MJ, Foody JM, Krumholz HM. The prognostic importance of anemia in patients with heart failure. Am J Med. 2003;114:

50. 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

51. Protocol Mancini Circ 2003;107
Randomized single blind prospective study in 27 HF patients
2:1 randomization
erythropoietin ,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%

52. Hemoglobin in Epo Group

53. Change in Peak VO2
P<0.02
Control
EPO

54. Control
Epo
*P<0.03
*P<0.01

55. Downward Spiral F A T I G U E Decreased CO Sympathetic Stimulation
Decrease SM Blood Flow
Vasoconstriction F A T I G U E
Inactivity
Cytokine Activation
Muscle wasting
Deconditioning
Anemia
Inactivity
Anorexia
Depression
More Muscle wasting
Decondtioning
Cachexia