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

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

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

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.

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 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 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

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

DEXA Scanning in CHF Anker AJC 99:83

NL CHF Mancini, Circ 1992;86:909

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 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 stain @pH 4.6 Mancini, Circ 1992;86:909

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

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

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

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

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

Chati, AHJ 1996;131:560

Coats, Circ 1992;85:2119

Mancini Circ 1992;86:909

Mancini Circ 1992;86:909

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

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

Nl Figure 1 Graphic 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 * 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

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

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

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

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

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

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 (1996-1997) 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;38:955-62. 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. 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 12 065 patients with new-onset heart failure. Circulation. 2003;107:223-225. 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;41:1933-1939. 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;38:955-962. 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;39:1780-1786. Kosiborod M, Smith GL, Radford MJ, Foody JM, Krumholz HM. The prognostic importance of anemia in patients with heart failure. Am J Med. 2003;114:112-119.

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

Protocol Mancini 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

Change in Peak VO2 P<0.02 Control EPO

Control Epo *P<0.03 *P<0.01

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