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

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Presentation on theme: "Causes of Fatigue in Patients with Heart Failure Donna Mancini, MD Columbia University New York, NY."— Presentation transcript:

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% Alzheimers-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 VO 2 vs those without Interventions associated with increase in VO 2 such as CRT are also associated with decrease in SDB Cheyne Stokes- Central Sleep Apnea

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

7 Lung Heart Muscle VO 2 = O 2 delivery-O 2 extraction VO 2 = CO * (A-VO 2 difference) O 2 delivery: Cardiac Output Pulmonary Function Hemoglobin Concentration O 2 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< 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 ( 31 P MRS)

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

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

15 DEXA Scanning in CHF Anker AJC 99:83

16 Mancini, Circ 1992;86:909 NL CHF

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 ATPase 4.6 NL CHF Mancini, Circ 1992;86:909

19 Enzyme ChangesFiber Type Changes

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

28 Recovery time provides an index of oxidative metabolism Independent of muscle mass CHF NL

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

30 Chati, AHJ 1996;131:560

31 Coats, Circ 1992;85:2119

32 Mancini Circ 1992;86:909


34 Low frequency fatigue does not occur

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

36 Figure 1 Graphic Nl HF 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 l Accelerated glycogen utilization in animal heart failure models l Reduced or low normal glycogen concentration in human heart failure skeletal muscle biopsies

44 POSSIBLE MECHANISMS OF ABNORMAL GLYCOGEN METABOLISM IN CHF: l Reduced delivery of substrates due to reduced muscle perfusion l Hormonal abnormalities -- elevated catecholamine levels l Intrinsic alteration of skeletal muscle metabolism with increased glycolytic activity a. deconditioning b. inhibition of free fatty acid metabolism

45 PROTOCOL JACC1999;34:1807 l Baseline: Day 1: Exercise performed in fasting state 60% protein 40% fat drink provided l Glycogen Depleted: Day 2: Exercise protocol repeated l 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 l Maximal: incremental bicycle exercise using 25W workloads of 3 minutes duration with measurement of respiratory gases l Submaximal: 75% of peak workload until exhaustion l 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 p=NS Peak VO2 (N=7) (N=13)

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 Anemia Is Common in Heart Failure Patients % of Heart Failure Patients With Anemia % Tang (N=2009) 1 Anker, ELITE (N=3044 Anker, ELITE (N=3044 ) 217% Ezekowitz, ICcodes(N=12,065) 317% Mozaffarian, PRAISE (N=1130) 420% 22% Al-Ahmad, SOLVD (N=6563) 5 28% Herzog, Medicare ICD (N=152,584) 6 30% Horwich, UCLA CM clinic (N=1061) 7 48% Kosiborod, Medicare (N=2281) 8 1. Tang WHW, et al. ACC Anker SD, et al. Circulation. 2002;106(suppl II):472. Abstract Ezekowitz JA, et al. Circulation. 2003;107: Mozaffarian D, et al. J Am Coll Cardiol. 2003;41: Al-Ahmad A, et al. J Am Coll Cardiol. 2001;38: Herzog CA, et al. J Card Fail. 2002;8(suppl):S63. Abstract Horwich TB, et al. J Am Coll Cardiol. 2002;39: Kosiborod M, et al. Am J Med. 2003;114: Prevalence varies with age, patient population, and definition of anemia.

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 * P<0.001

53 Control EPO Change in Peak VO 2 P<0.02

54 ControlEpo * P<0.03 * P<0.01

55 Downward Spiral Decreased CO Sympathetic Stimulation Decrease SM Blood Flow Vasoconstriction Inactivity Cytokine Activation Muscle wasting Deconditioning Anemia Inactivity Anorexia Depression More Muscle wasting Decondtioning Cachexia FATIGUEFATIGUE

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