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Causes of Fatigue in Patients with Heart Failure

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

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Causes of Fatigue in Patients with Heart Failure

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  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. 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% Non-Cardiac CoMorbidities in Patients >65 yrs with CHF (n=122,630) Braunstein, JACC 2003;42: 1793

  5. • 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. 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

  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 HypothesisMuscle as a Sensory Organ Muscle Atrophic Deconditioned Metabolically abnl Hypoxia Exercise Afferents Breathlessness Fatigue

  14. 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 Type I and II Atrophy  Type II b  Type I  oxidative enzymes  mitochondria volume NL CHF CHF ATPase stain @pH 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

  25. Kao W, AJC 1995;76:606

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

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

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

  29. Chati, AHJ 1996;131:560

  30. Coats, Circ 1992;85:2119

  31. Mancini Circ 1992;86:909

  32. Mancini Circ 1992;86:909

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

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

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

  36. Tikunov Circ 1997;95

  37. 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

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

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

  40. 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

  41. Nutrient Use During Exercise

  42. 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

  43. 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

  44. 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

  45. 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

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

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

  48. Tang (N=2009)1 16% Anker, ELITE (N=3044)2 17% Ezekowitz, ICcodes(N=12,065)3 17% Mozaffarian, PRAISE (N=1130)4 20% Al-Ahmad, SOLVD (N=6563)5 22% Herzog, Medicare ICD (N=152,584)6 28% Horwich, UCLA CM clinic (N=1061)7 30% Kosiborod, Medicare (N=2281)8 48% Anemia Is Common in Heart Failure Patients Prevalence varies with age, patient population, and definition of anemia. 0 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;38:955-62. 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. 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.

  49. 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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