Exercise Intolerance in Heart Failure: Significance of Skeletal Muscle Abnormalities

Transcription

1 Exercise Intolerance in Heart Failure: Significance of Skeletal Muscle Abnormalities Hokkaido University Graduate School of Medicine Shintaro Kinugawa

2 Survival rate (%) Peak oxygen uptake and prognosis in patients with heart failure (HF) 1 75 Peak Oxygen Uptake (VO 2 ) (ml/kg/min) >18 >14 18 > Follow up (Months) Mancini DM, et al. Circulation 1991; 83:

3 Factors regulating exercise capacity Peripheral circulation Pulmonary circulation Mitochondria CO 2 production Skeletal muscle O 2 consumption O 2 transport Heart Blood CO 2 transport Expiration Lung Inspiration VCO 2 VO 2 Small Reserve capacity Large

4 HF is a systemic disorder HF Metabolic disorder Depression Anemia Cardiac dysfunction Skeletal muscle abnormalities Activation of neurohumoral factors CKD Endothelial dysfunction Immunological disorder Sleep disordered breathing

5 Exercise capacity and pathology of HF

6 Survival rate (%) Aerobic exercise training improves survival rate in patients with HF (ExTraMATCH) 1 9 Training Control Follow up (days) Modified, Piepoli MF. BMJ 24; 328: 189

7 Effects of exercise therapy for heart failure 1. Improve exercise capacity (peak VO 2, AT) 2. Minor change in cardiac function (LV systolic function and remodeling) 3. Improve endothelial function (Coronary and peripheral circulation) 4. Improve ventilation 5. Improve autonomic nerves function 6. Improve skeletal muscle abnormalities Exercise therapy is a highly ideal treatment for HF and is a standard of care.

8 VO 2 (ml/min) Lactate (mg/dl) Leg blood flow (L/min) O 2 extraction (%) Dobutamine does not increase exercise capacity Control Dobutamine Rest Submax Max Rest Submax Max Rest Submax Max Rest Submax Max Wilson JR, et al. Am J Cardiol. 1984; 53:

9 (ml/kg/min) Does heart regulate peak whole body exercise capacity? Leg bicycle ergometer Arm bicycle ergometer 3 Increase in VO 2 2 Added arm bicycle ergometer when AT is exceeded 1 The heart is not reaching the limit at the limit of exercise (peak VO 2 ) as severe heart failure <15 >15 Normal Peak VO 2 Jondeau G, et al. Circulation 1992; 11: 219S-222S

10 Skeletal muscle is impaired in patients with HF HF HF Skeletal muscle metabolism Control Control Decreased mitochondrial enzyme (cyto C) Drexler H, et al. Circulation 1992; 85: Decreased slow twitch fiber and capillary Sabbah HN, et al. Circulation 1993; 87: Impaired metabolism independent on blood flow Okita K, et al. Circulation 1998; 98:

11 Energy metabolism in the skeletal muscle during exercise in HF patients Skeletal muscle cells Fatty acid 1 H-MRS Muscle contraction Peak VO 2 Exercise capaciy β-oxidation IMCL PCr O 2 H 2 O ATP Cr + Pi 31 P-MRS Mitochondria PCr, phosphocreatine; Pi, inorganic phosphate; Cr, creatine; IMCL, intramyocellular lipid

12 What is happening in skeletal muscle during whole body exercise? Whole body MR system Rapid inflator

13 PCr depletion at peak exercise ph=7.2 Normal subject PCr ph=7.7 CHF patient PCr Rest Pi γ ATP α β Pi γ ATP α β Pi ph=6.63 Pi ph=6.42 Peak Exercise PCr PCr chemical shift (ppm) chemical shift (ppm) (Okita K. Circulation, 1998) Okita K, et al. Circulation 1998; 98:

14 Muscle Impaired metabolism skeletal during muscle systemic metabolism exercise Rest Phosphocreatine CHF Controls Rest CHF Muscle ph Controls Vo 2 (ml/min/kg) Vo 2 (ml/min/kg - ) p<.5 Fig 2-2. Muscle metabolism during maximal bicycle exercise. The phosphocreatine was nearly depleted at peak exercise in both groups. Muscle ph was more severely decreased in patients than in controls.. Decreases in phosphocreatine and ph are larger in patients with HF. Okita K, et al. Circulation 1998; 98:

15 IMCL (mmol/kg wet weight) Intramyocellular lipid (IMCL) EMCL IMCL 8 Control TCr 6 IMCL 4 HF TCr EMCL Control HF ppm Hirabayashi K, et al. Int J Cardiol 214;176:111-2

16 Peak VO 2 (ml/kg/min) AT (ml/kg/min) PCr loss (%) Association between IMCL and exercise capacity Control (n=12) HF (n=18) r=-.589, p<.1 r=-.62, p<.1 r=.63, p< IMCL content (mmol/kg wet weight) IMCL content (mmol/kg wet weight) IMCL content (mmol/kg wet weight) Hirabayashi K, et al. Int J Cardiol 214;176:111-2

17 Survival rate (%) 1 Muscle strength and survival rate 8 High strength (n=49) 6 4 Low strength (n=42) Follow up (months) Survival rate is lower in low knee flexors strength group (<68NmX1/kg) than in high group. Hülsmann M, et al. Eur J Heart Fail 24; 6: 11-7

18 Handgrip (kg) Quadriceps (kg) Peak VO 2 (ml/kg) Exercise time (min) Skeletal muscle mass and muscle strength/endurance capacity Muscle strength Endurance capacity Muscle atrophy Muscle atrophy Muscle atrophy Muscle atrophy Fulster S, et al. Eur Heart J. 213;34:512-9

19 Cardiac event free (%) Sarcopenia and HF Elderly people aged 6 to 7 years with sarcopenia are 5 to 13 %. von Haehling S. et al. Int J Biochem Cell Biol. 213; 45: HF patients (mean age of 66.9) with sarcopenia are 19.5%. Fulster S, et al. Eur Heart J. 213;34: ー Sarcopenia (-) ー Sarcopenia (+) Follow up (day) Onoue Y, et al. Int J Cardiol. 216; 215: 31-6

20 Skeletal muscle abnormalities in HF Morphology Histology Biochemistry Others Muscle wasting Muscle fiber atrophy (IIb) Type I fibers Type II fibers Shift from type IIa to IIb Oxidative enzymes Glycolytic enzymes Impaired energy metabolism Ergoreflex Capillary density Shift from MHC1 to MHC2 Mitochondrial volume enos Apoptosis Skeletal muscle abnormalities are largely associated with the limited exercise capacity in patients with HF and are the target of exercise therapy. Impaired mitochondrial function and decrease in mitochondrial volume Muscle atrophy and decrease in muscle strength Okita K, et al. Circ J 213; 77: 293-3

21 Signal regulating mitochondrial biogenesis RAS AdipoR1 enos AT1R Nox [Ca 2+ ] CaMKK AMP ATP NAD + NADH NO CaMK AMPKα SIRT1 ROS Transcription PGC1α p38mapk Nucleus Electron transport chain Mitochondrion β-oxidation β-had Acetyl-CoA TCA cycle SIRT3 NAD + FAD ADP+Pi NADH FADH 2 ATP CO 2 NADH NAD + I II III Cyt c IV H + H + H + ADP +Pi F V F 1 ATP Intermembrane space Matrix Kinugawa et al. Int Heart J 215; 56:475-84

22 Signal regulating protein synthesis and degradation IGF1 Myostatin RAS TNFα Glucocorticoid IGF1R ActRIIB AT1R Nox TNFR GR Smad2/3 ROS IKK PI3K Akt IκB GSK3β mtor p38 MAPK mtorc1 mtorc2 NFκB eif2b p7s6k1 4E-BP FoxO S6 eif4e Atrogin 1 MuRF1 Protein synthesis Protein degradation Translation Kinugawa et al. Int Heart J 215; 56:475-84

23 Muscle cross sectional area (μm 2 ) Body weight (g) skeletal muscle weight (mg) Ang II induces muscle atrophy in mice Vehicle Ang II 1 wk 4 wks 1 week 4 weeks week 1 wk 4 4 weeks wks 1 week 4 weeks 25 Vehicle Ang II μm 11 week wk 4 weeks wks Kadoguchi T, et al. Exp Physiol 215; 1:

24 Type I (%) Type IIa (%) Type IIb (%) CS activity (nmol/min/mg protein) Complex I (nmol/min/mg protein) Complex III (nmol/min/mg protein) Ang II induces mitochondrial dysfunction in skeletal muscle and transition of fiber type Vehicle Ang II week wk 4 weeks wks 11 week wk 44 weeks wks 11 week wk 4 weeks wks 1 wk 4 wks Vehicle Ang II Type I Type IIb Type IIa 1 μm 11 week wk 4 weeks wks 11 week wk 4 weeks wks 11 week wk 4 weeks wks Kadoguchi T, et al. Exp Physiol 215; 1:

25 TUNEL positive nuclei (%) Cleaved caspase-3/gapdh Ang II induces apoptotic cell death in skeletal muscle 1 wk 4 wks 1 wk 4 wks Vehicle Cleaved caspase-3 GAPDH Ang II Vehicle Ang II 1 μm week wk 4 weeks wks 11 week wk 44 weeks wks Kadoguchi T, et al. Exp Physiol 215; 1:

26 Lucigenin chemiluminescence (RLU/min/mg) NAD(P)H oxidase activity (RLU/min/1µg protein) Ang II enhances ROS by activated NAD(P)H oxidase in skeletal muscle 2 Vehicle Ang II week wk 44 weeks wks 11 week wk 44 weeks wks Kadoguchi T, et al. Exp Physiol 215; 1:

27 Ang II induces all skeletal muscle abnormalities clinically observed in HF Morphology Histology Biochemistry Others Muscle wasting Muscle fiber atrophy (IIb) Type I fibers Type II fibers Shift from type IIa to IIb Oxidative enzymes Glycolytic enzymes Impaired energy metabolism Ergoreflex Capillary density Shift from MHC1 to MHC2 Mitochondrial volume enos Apoptosis Ang II ROS Skeletal muscle abnormalities Okita K, et al. Circ J 213; 77: 293-3

28 Skeletal muscle is a huge endocrine organ Pedersen BK, et al. Nat Rev Endocrinol 212; 8:

29 Conclusion Skeletal muscle abnormalities play an important role in the pathogenesis of HF. However, no therapy targeting skeletal muscle abnormalities has been developed. Developing new drug therapy may be useful for treatment of patients with severe HF who can not perform exercise. We need to clarify the mechanism for skeletal muscle abnormalities in HF and to develop new treatment targeting them.