Endurance training in systolic heart failure.

Transcription

1 Endurance training in systolic heart failure. Nicolle Kränkel, PhD, Dipl.-Ing. (FH) University of Zurich, Institute of Physiology & UniSpital Zürich, Division of Cardiology No relationships to disclose.

2 dysfunction or destruction of cardiac myocytes or their molecular components decreased ejection fraction (< 45%) variety of causes: congenital (muscular dystrophy) inflammation /cellular infiltration (myocarditis, amyloidosis) toxins/ pharmacological agents (ethanol, cocaine, amphetamines) ischemia/scar formation (myocardial infarction) Image adapted from: Beers MH (editor). The Merck Manual of Diagnosis and Therapy. 2006

3 Exercise Capacity in Chronic Heart Failure Exercise capacity is severely reduced in CHF. Reduced exercise capacity contributes to reduced quality of life and to increased morbidity & mortality. Reduced pump function is not the sole responsible factor. Instead, alterations in skeletal & cardiac muscle histology, inflammatory status, vascular function, metabolic and neurohumoral dysregulation, and others.

4 Effects of exercise training in CHF: Target organs neurohumoral: reduced vagal activation cardiac: reduced catabolism better perfusion heart rate / b-ar signaling improved ventilatory: reduced catabolism metabolism: altered glucose and lipid metabolism altered adipose tissue histology vascular: enhanced antioxidative enzymes (SOD) reduced inflammation inproved endothelial function skeletal muscle: reduced catabolic pathways (fiber type shift) reduced inflammation increased capillarization/perfusion

5 Cardiac effects of exercise training: Functional improvement LV remodelling CHF Reduced pump function Reduced capillarization Heart rest Heart peak exercise b-adrenergic receptors sympathetic nervous system CHF + exercise Limits further LV dilation hypertrophic response catabolic pathways inflammatory cytokines contractility capillarization in borderzone & remote area Heart rest Heart peak exercise b-adrenergic receptors sympathetic nervous system

6 sham operated LAD ligation control CHF sedentary treadmill exercise characterization of cardiac muscle Leosco et al. Cardiovasc Res. 2008

7 remote border (LV ant) border (LV lat) Institute of Physiology capillary density [n per cm 2 ] capillary / myocyte ratio Leosco et al. Cardiovasc Res SED control EX SED EX SED EX SED EX HF control HF

8 Cardiac effects of exercise training: Functional improvement LV remodelling CHF Reduced pump function Reduced capillarization Heart rest Heart peak exercise b-adrenergic receptors sympathetic nervous system CHF + exercise Limits further LV dilation hypertrophic response catabolic pathways inflammatory cytokines contractility capillarization in borderzone & remote area Heart rest Heart peak exercise b-adrenergic receptors sympathetic nervous system

9 Lenk et al. Eur J Heart Fail Institute of Physiology Cardiac effects: Reduced catabolism sham operated LAD ligation control CHF sedentary treadmill exercise characterization of cardiac muscle

10 Muscular effects of exercise training CHF Deconditioning (due to shortness of breath & fatigue) Muscle atrophy Structural modifications (linked especially to malnutrition, deconditioning and the toxic action of cytokines) Type I oxidative fibres Type IIB fibres (glycolytic fibres) Mitochondrial density Enzymes involved in the Krebs cycle (i.e., the oxidative pathway) Capillary density CHF + exercise Muscular activity Catabolic pathways & apoptosis Atrophy Inflammatory cytokines Cross-secional area, strength & endurance Oxidative fibers (type I) Glycolytic fibers (type II) Oxidative activity No. of mitochondria Capillary density low-intensity, short duration moderate -high intensity longer duration

11 Muscular effects of exercise training: Reduced catabolic signaling cardiac-specific overexpression of calsequestrin control CHF exercise intolerance cachexia skeletal muscle vascular rarefaction skeletal muscle atrophy expression of MafBx (atrogin-1) Li et al. Am J Pathol. 2007

12 Muscular effects of exercise training: Reduced catabolic signaling cardiac-specific overexpression of calsequestrin control CHF exercise intolerance cachexia skeletal muscle vascular rarefaction skeletal muscle atrophy expression of MafBx (atrogin-1) Li et al. Am J Pathol. 2007

13 The Ubiquitin - Proteasome - System In skeletal muscle/chf: MuRF-1 MAFbx/atrogin-1

14 Gielen et al. Circulation Institute of Physiology Muscular effects of exercise training: Reduced catabolic signaling healthy CHF <55years >65years <55years >65years ET SED ET SED ET SED ET SED Exercise protocol (4 weeks ): 4 supervised training sessions á 20 min per week on a bicycle 70% of the symptom-limited VO 2 max plus 1 group training session of 60 minutes per week

15 VO 2 max [ml/kg*min] Institute of Physiology Muscular effects of exercise training: Reduced catabolic signaling CHF 30 young old <55years >65years * * ET SED ET SED Exercise protocol (4 weeks ): 4 supervised training sessions á 20 min 5x per week on a bicycle 70% of the symptom-limited VO 2 max plus 1 group training session of 60 minutes per week beg end beg end beg end beg end ET - HF SED - HF ET - HF SED - HF Gielen et al. Circulation. 2012

16 Gielen et al. Circulation Institute of Physiology Muscular effects of exercise training: Reduced catabolic signaling healthy CHF <55years >65years <55years >65years ET SED ET SED ET SED ET SED MuRF-1 expression

17 Gielen et al. Circulation Institute of Physiology Muscular effects of exercise training: Reduced catabolic signaling Protein ubiqutinylation

18 quadriceps CSA[cm2] Höllriegel et al. Int J Cardiol Institute of Physiology Muscular effects of exercise training in advanced CHF (NYHA IIIb) CHF (NYHA IIIb) MuRF-1 * ET SED control Exercise protocol (12 weeks): on a bicycle ergometer in-hospital (3 weeks): 3-6 x daily 5-20 heart rate ~ 50% of the VO 2 max at home (9 weeks): daily heart rate ~ 60% of VO 2 max MAFbx 0 months 3 months 0 months 3 months control exercise

19 Inflammatory circulating factors Inflammatory cytokines (TNF-a, IL-6), soluble receptors & ligands (TNF-Rs, FasL), microparticles increased in CHF [Oruset al. 2000; Rauchhaus et al. 2000; Gielen et al. 2003; and others] Correlation between serum cytokines (TNF-a) and NYHA class / negative correlation with exercise capacity [Cicoira et al. 2001; Gielen et al. 2003; Byrkjeland et al. 2011; and others] Exercise training reduces circulating levels of cytokines & cytokine receptors [Adamopoulos et al. 2001; Bjørnstad et al. 2008; and others]

20 Inflammatory circulating factors However: Not all studies report reduced cytokine levels by ET in CHF. Degree of attenuation of the pro-inflammatory response may depend on the mode of training. [LeMaitre et al. 2004] Etiology of CHF determines downregulation of inflammatory cytokines [Byrkjeland et al ] TNF-a or IL-6 decrease did not correlate with clinical, demographic or pharmacological parameters, but previous MI, longer exercise sessions & BMI predict change in TNF-a [Smart et al. 2011] Reduction of cytokines greater in terminal phase, where patients experience more severe symptoms, than in earlier phases, where symptoms are mild to moderate [Smart et al. 2011]

21 Circulating inflammatory mediators: Vascular effects Inflammatory cytokines promote atherosclerosis & adverse vascular remodelling via increase of oxidative stress, decrease of NO availability, increased vasoconstriction, increased EC apoptosis [Tousoulis et al. 2005; Ichihara et al. 2006; Parodi et al. 2007; Adamopoulos et al. 2002; Adamopoulos et al. 2003] Circulating microparticles may promote thrombosis, but have also been shown to induce protection against apoptosis & induction of vaso-regenerative potential - Much work still to be done!! [Nieuwland et al. Circulation. 1997; Mallat et al. Circulation 1998; Mause et al. Circulation. 2010; and others]

22 Vascular effects of exercise training in CHF CHF atherosclerosis with: NO generation endothelium-dependent vasodilation capillary density CHF + exercise (laminar) shear stress leading to: NO generation endothelium-dependent vasodilation capillarization perfusion peripheral resistance (afterload) oxidative stress anti-oxidative capacity cytokine generation endothelial homeostasis & quiescence monocyte adhesion

23 Vascular effects of exercise training in CHF: Shear stress Davis et al. J Biol Chem shear stress Dimmeler et al. Nature activation of enos transcription & phosphorylation nucleus IkK/ NFkB endothelial cell

24 Vascular effects of exercise training in CHF patients with stable CAD scheduled for elective bypass surgery p-akt p-enos ET 4 weeks 6 x daily 10 min workload below chest pain SED control usual care obtain remnant of mammaria interna, left over after bypass surgery assess endothelial-mediated vasodilation and molecular parameters Hambrecht et al. Circulation. 2003

25 change in vessel diameter vs. baseline [%] Institute of Physiology Vascular effects of exercise training in CHF patients with stable CAD scheduled for elective bypass surgery ET SED control sedentary control begin sedentary control 4 weeks exercise begin exercise 4 weeks * P<0.05 vs. control 4 weeks 6 x daily 10 min workload below chest pain usual care * * obtain remnant of mammaria interna, left over after bypass surgery assess endothelial-mediated vasodilation and molecular parameters * concentration ACh [ug/min] Hambrecht et al. Circulation. 2003

26 Vascular effects of exercise training in CHF CHF atherosclerosis with: NO generation endothelium-dependent vasodilation capillary density CHF + exercise (laminar) shear stress leading to: NO generation endothelium-dependent vasodilation capillarization perfusion peripheral resistance (afterload) oxidative stress anti-oxidative capacity cytokine generation endothelial homeostasis & quiescence monocyte adhesion

27 GPx1 mrna (AU) SOD2 mrna (AU) SOD1 mrna (AU) Institute of Physiology Vascular effects of exercise training in CHF: Induction of antioxidant defense healthy previously untrained (<2h activity/week), age ~30y, BMI < 27 kg/m2 previously trained (>6h activity/week) untrained trained ET ET + Vit.C ET ET + Vit.C Exercise protocol (4 weeks): supervised 5 days / submaximal heart rate each session: 20 min of biking or running 45 min of circuit training 20 min periods for warming up / cooling down Ristow et al. Proc Natl Acad Sci U S A. 2009

28 Vascular effects of exercise training in CHF: Induction of antioxidant defense Ristow et al. Proc Natl Acad Sci U S A. 2009

29 Summary: Effects of exercise training in CHF Symptoms/ functional parameters: improved VO 2 max reduced mortality Skeletal muscle: atrophy stopped less inflammatory cytokines Heart: atrophy stopped better perfusion reduced symathic activation Respiration: atrophy stopped exercise modalities etiology / stage of HF Circulation/ Blood vessels: (reduced inflammatory load) improved NO availability oxidative defense induced improved vagal control Metabolism: improved insulin sensitivity Immune system: macrophage activation reduced

30 Thanks!!! UniSpital Zürich & University of Zurich: Ulf Landmesser Thomas Lüscher Kira Kuschnerus Maja Müller Sylvie Briand Meliana Riwanto Michaela Keel

31 Circulating inflammatory mediators: Microparticles small membranous vesicles (< 1um) transport proteins / nucleic acids / lipids between cells shed by activated cells (e.g. platelets, leukocytes, endothelial cells increased in coronary artery disease, stroke & MI

32 Chaar et al. Clin Hemorheol Microcirc Institute of Physiology Circulating inflammatory mediators: Microparticles Effect of strenuous physical exercise on circulating cell-derived microparticles. young healthy individuals (age ~19 years) 3-min warm-up at 60Wand the load was increased by 30W every minute until VO2max was reached

33 Sossdorf et al. Med Sci Sports Exerc Institute of Physiology Circulating inflammatory mediators: Microparticles Prothrombinase activity of microparticles before / after acute exercise young healthy individuals (age ~25 years) single bout of endurance exercise on a bicycle ergometer with a constant power of 80% individual anaerobic threshold for a period of 90 min

34 Nozaki et al. Eur J Heart Fail Institute of Physiology Circulating inflammatory mediators: Microparticles Endothelial microparticles Cardiovascular event-free survival Protection from atherosclerosis vs. mediating pro-coagulative state??? Altered molecular effects or only numbers in CHF? Effect of exercise training/training modalities?

35 Exercise Training in Chronic Heart Failure Drawbacks Benefits

36 gender (?) age underlying diseases / severity of symptoms accompanying medication (?) exercise protocol compliance vs. Benefits Benefits

37 J Am Coll Cardiol Nov 16;56(21): Depression as a potential modulator of Beta-adrenergic-associated leukocyte mobilization in heart failure patients. Redwine LS, Wirtz PH, Hong S, Bosch JA, Ziegler MG, Greenberg B, Mills PJ. Source Department of Psychiatry, University of California, San Diego, La Jolla, California 92161, USA. lredwine@ucsd.edu Erratum in J Am Coll Cardiol May 10;57(19):1960. Bosch, Jos [corrected to Bosch, Jos A]. Abstract OBJECTIVES: the aim of this study was to determine whether depressive symptoms are related to alterations in the sensitivity of peripheral blood mononuclear cells to β-adrenergic agonists in patients with heart failure (HF) by measuring in vitro chemotaxis (CTX) to isoproterenol at rest and after acute exercise in patients with HF and controls. BACKGROUND: clinical outcomes are worse for patients with HF presenting with symptoms of depression. Sympathetically modulated immune dysregulation associated with depression may be one mechanism leading to worse prognosis. METHODS: seventy-seven patients with HF and 44 controls (mean age 56.4 ± 1.3 years) completed the Beck Depression Inventory and a 15-min mild-graded exercise task on a stationary bicycle. Exercise intensity was kept relative to fitness levels for all participants by gradually increasing resistance to reach a Borg scale subjective rating of 12 to 13, "somewhat hard." Plasma norepinephrine and epinephrine levels were measured before and after exercise. Chemotaxis to isoproterenol was determined by measuring in vitro peripheral blood mononuclear cell migration through a modified Boyden chamber. RESULTS: In patients with HF, depressive symptom severity was associated with greater CTX after exercise (p = 0.001). Higher resting norepinephrine in patients with HF was also associated with increased CTX to exercise (p = 0.03). CONCLUSIONS:

38 Gielen et al. Circulation Institute of Physiology Muscular effects of exercise training

39 Functional parameter: Force endurance

40

41 Diabetes Aug;56(8): Epub 2007 May 18. Effects of endurance exercise training on insulin signaling in human skeletal muscle: interactions at the level of phosphatidylinositol 3-kinase, Akt, and AS160. Frøsig C, Rose AJ, Treebak JT, Kiens B, Richter EA, Wojtaszewski JF. Source Copenhagen Muscle Research Centre, Section of Human Physiology, Department of Exercise and Sport Sciences, University of Copenhagen, Copenhagen, Denmark. Abstract The purpose of this study was to investigate the mechanisms explaining improved insulin-stimulated glucose uptake after exercise training in human skeletal muscle. Eight healthy men performed 3 weeks of one-legged knee extensor endurance exercise training. Fifteen hours after the last exercise bout, insulin-stimulated glucose uptake was approximately 60% higher (P < 0.01) in the trained compared with the untrained leg during a hyperinsulinemic-euglycemic clamp. Muscle biopsies were obtained before and after training as well as after 10 and 120 min of insulin stimulation in both legs. Protein content of Akt1/2 (55 +/- 17%, P < 0.05), AS160 (25 +/- 8%, P = 0.08), GLUT4 (52 +/- 19%, P < 0.001), hexokinase 2 (HK2) (197 +/- 40%, P < 0.001), and insulin-responsive aminopeptidase (65 +/- 15%, P < 0.001) increased in muscle in response to training. During hyperinsulinemia, activities of insulin receptor substrate-1 (IRS-1)-associated phosphatidylinositol 3-kinase (PI3-K) (P < 0.005), Akt1 (P < 0.05), Akt2 (P < 0.005), and glycogen synthase (GS) (percent I-form, P < 0.05) increased similarly in both trained and untrained muscle, consistent with increased phosphorylation of Akt Thr(308), Akt Ser(473), AS160, glycogen synthase kinase (GSK)-3alpha Ser(21), and GSK-3beta Ser(9) and decreased phosphorylation of GS site 3a+b (all P < 0.005). Interestingly, training improved insulin action on thigh blood flow, and, furthermore, in both basal and insulin-stimulated muscle tissue, activities of Akt1 and GS and phosphorylation of AS160 increased with training (all P < 0.05). In contrast, training reduced IRS-1-associated PI3-K activity (P < 0.05) in both basal and insulin-stimulated muscle tissue. Our findings do not support generally improved insulin signaling after endurance training; rather it seems that improved insulin-stimulated glucose uptake may result from hemodynamic adaptations as well as increased cellular protein content of individual insulin signaling components and molecules involved in glucose transport and metabolism.

42 Mayo Clin Proc Jun;87(6): Potential adverse cardiovascular effects from excessive endurance exercise. O'Keefe JH, Patil HR, Lavie CJ, Magalski A, Vogel RA, McCullough PA. Source Mid America Heart Institute of Saint Luke's Hospital of Kansas City, MO, USA. Abstract A routine of regular exercise is highly effective for prevention and treatment of many common chronic diseases and improves cardiovascular (CV) health and longevity. However, long-term excessive endurance exercise may induce pathologic structural remodeling of the heart and large arteries. Emerging data suggest that chronic training for and competing in extreme endurance events such as marathons, ultramarathons, ironman distance triathlons, and very long distance bicycle races, can cause transient acute volume overload of the atria and right ventricle, with transient reductions in right ventricular ejection fraction and elevations of cardiac biomarkers, all of which return to normal within 1 week. Over months to years of repetitive injury, this process, in some individuals, may lead to patchy myocardial fibrosis, particularly in the atria, interventricular septum, and right ventricle, creating a substrate for atrial and ventricular arrhythmias. Additionally, long-term excessive sustained exercise may be associated with coronary artery calcification, diastolic dysfunction, and large-artery wall stiffening. However, this concept is still hypothetical and there is some inconsistency in the reported findings. Furthermore, lifelong vigorous exercisers generally have low mortality rates and excellent functional capacity. Notwithstanding, the hypothesis that long-term excessive endurance exercise may induce adverse CV remodeling warrants further investigation to identify at-risk individuals and formulate physical fitness regimens for conferring optimal CV health and longevity.

43 J Card Fail Sep;1(4): Skeletal muscle fiber composition and capillarization in patients with chronic heart failure: relation to exercise capacity and central hemodynamics. Schaufelberger M, Eriksson BO, Grimby G, Held P, Swedberg K. Patients with chronic heart failure have structural and metabolic changes in skeletal muscle, which may be of importance for symptomatology. The origin of these changes are still unknown. The relationship between fiber composition and capillarization in skeletal muscle with exercise capacity and central hemodynamic variables was examined. Biopsies from the lateral vastus muscle were taken in 12 patients with chronic heart failure. Samples from eight normal subjects served as control samples. All patients underwent maximal exercise tests. Central hemodynamic variables were measured during exercise in five patients. The patients had a higher percentage of type II B fibers (P =.03) and fewer capillaries per fiber (P =.02) than the controls subjects. VO2 max correlated with the percentage of type I fibers, whereas the correlation with the type II A fibers was inverse. Cardiac index and pulmonary capillary wedge pressure at submaximal and maximal exercise were related to fiber type composition and relative fiber areas. Skeletal muscle fiber type composition and capillarization was changed in patients with chronic heart failure. These changes might influence exercise capacity. There were relationships between central hemodynamic variables and skeletal muscle changes. What the cause and effects were need further investigation.

44 Circ Heart Fail Nov;2(6): Epub 2009 Sep 24. Mechanisms underlying skeletal muscle weakness in human heart failure: alterations in single fiber myosin protein content and function. Miller MS, Vanburen P, Lewinter MM, Lecker SH, Selby DE, Palmer BM, Maughan DW, Ades PA, Toth MJ. BACKGROUND: Patients with chronic heart failure (HF) frequently experience skeletal muscle weakness that limits physical function. The mechanisms underlying muscle weakness, however, have not been clearly defined. METHODS AND RESULTS: This study examined the hypothesis that HF promotes a loss of myosin protein from single skeletal muscle fibers, which in turn reduces contractile performance. Ten patients with chronic HF and 10 controls were studied. Muscle atrophy was not evident in patients, and groups displayed similar physical activity levels, suggesting that observed differences reflect the effects of HF and not muscle atrophy or disuse. In single muscle fibers, patients with HF showed reduced myosin heavy chain protein content (P<0.05) that manifested as a reduction in functional myosin-actin cross-bridges (P<0.05). No evidence was found for a generalized loss of myofilament protein, suggesting a selective loss of myosin. Accordingly, single muscle fiber maximal Ca(2+)-activated tension was reduced in myosin heavy chain I fibers in patients (P<0.05). However, tension was maintained in myosin heavy chain IIA fibers in patients because a greater proportion of available myosin heads were bound to actin during Ca(2+) activation (P<0.01). CONCLUSIONS: Collectively, our results show that HF alters the quantity and functionality of the myosin molecule in skeletal muscle, leading to reduced tension in myosin heavy chain I fibers. Loss of single fiber myosin protein content represents a potential molecular mechanism underlying muscle weakness and exercise limitation in patients with HF.

45 PLoS One May 7;3(5):e2086. Fiber type-specific nitric oxide protects oxidative myofibers against cachectic stimuli. Yu Z, Li P, Zhang M, Hannink M, Stamler JS, Yan Z. Oxidative skeletal muscles are more resistant than glycolytic muscles to cachexia caused by chronic heart failure and other chronic diseases. The molecular mechanism for the protection associated with oxidative phenotype remains elusive. We hypothesized that differences in reactive oxygen species (ROS) and nitric oxide (NO) determine the fiber type susceptibility. Here, we show that intraperitoneal injection of endotoxin (lipopolysaccharide, LPS) in mice resulted in higher level of ROS and greater expression of muscle-specific E3 ubiqitin ligases, muscle atrophy F-box (MAFbx)/atrogin-1 and muscle RING finger-1 (MuRF1), in glycolytic white vastus lateralis muscle than in oxidative soleus muscle. By contrast, NO production, inducible NO synthase (inos) and antioxidant gene expression were greatly enhanced in oxidative, but not in glycolytic muscles, suggesting that NO mediates protection against muscle wasting. NO donors enhanced inos and antioxidant gene expression and blocked cytokine/endotoxin-induced MAFbx/atrogin-1 expression in cultured myoblasts and in skeletal muscle in vivo. Our studies reveal a novel protective mechanism in oxidative myofibers mediated by enhanced inos and antioxidant gene expression and suggest a significant value of enhanced NO signaling as a new therapeutic strategy for cachexia.

46 Muscular effects of exercise training Adams V, Yu J, Möbius-Winkler S, Linke A, Weigl C, Hilbrich L, Schuler G, Hambrecht R. Increased inducible nitric oxide synthase in skeletal muscle biopsies from patients with chronic heart failure. Biochem Mol Med Aug;61(2): J Am Coll Cardiol Mar 15;33(4): Apoptosis in skeletal myocytes of patients with chronic heart failure is associated with exercise intolerance. Adams V, Jiang H, Yu J, Möbius-Winkler S, Fiehn E, Linke A, Weigl C, Schuler G, Hambrecht R.

47 Muscular effects of exercise training: oxidative capacity muscular activity oxidative activity oxidative fibers (type I), glycolytic fibers (type II) catabolic pathways & apoptosis, atrophy cross-secional area, strength & endurance workload per individual fiber capillary density inflammatory cytokines

48 Alterations in myocardial protein expression in CHF control early HF late HF sham operated LAD ligation ox. stress small HSP SOD 2 /Gpx1 Gpx1 complex control CHF characterization of LV protein expression metabolism fatty acid metabolism tricarboxylic acid cycle ATP a ATP D glycolysis Cieniewski-Bernard et al. J Proteome Res. 2008

49 fiber size type [um] [%] Institute of Physiology Muscular effects of exercise training patients with a history of mild CHF classified into a training group and a control group matched for clinical and functional characteristics at 40% of peak oxygen uptake three times a week for 8 weeks analysis of skeletal muscle biopsies obtained before and after study period type I type II * * Before After After Before Before After After control control exercise exercise type I type II Belardinelli et al. J Am Coll Cardiol. 1995

50 0 months 3 months 6 months 0 months 3 months 6 months fiber type [%] Institute of Physiology Muscular effects of exercise training patients CHF NYHA II/III randomized into a training group and a control group exercise at HR corresponding to 50-60% of peak oxygen uptake 3 months supervised training + 3months self-training = total 6 months analysis of skeletal muscle biopsies obtained before and after study period fiber size [x10^3 um^2] months type II type II II 3 months 6 months 0 months control control 3 months 6 months exercise exercise Kiilavuori et al. Eur J Heart Fail 2000

51 Byrkjeland et al. Scand J Clin Lab Invest Nov;71(7): Epub 2011 Aug 11. Inflammatory markers as related to disease severity in patients with chronic heart failure: limited effects of exercise training. R, Nilsson BB, Westheim AS, Arnesen H, Seljeflot I. BACKGROUND: Chronic heart failure (CHF) is associated with increased inflammation, and exercise training has in some studies been shown to have anti-inflammatory effect, although controversies exist. We investigated the effects of exercise training in CHF patients on markers of inflammation, and further explored any association between inflammation and the severity and etiology of the disease. METHODS: Eighty patients in stable CHF were randomized to 4 months of group-based high intensity exercise training or to a control group. Physical capacity was measured by 6-minute walk test and cycle ergometer test. Blood samples were drawn at baseline, after 4 months and after 12 months follow-up for analyses of a range of biomarkers. RESULTS: Physical capacity was significantly inversely related to CRP, IL-6, VCAM-1 and TGF-β, and NT pro-bnp levels were significantly correlated to CRP, TNF-α, IL-6, VCAM-1, ICAM-1 and TGF-β (p < 0.05 for all). Patients with hypertension as etiology of CHF showed higher levels of CRP (p < 0.01), IL-6 (p = 0.05) and TNF-α (p = 0.02) as compared to other etiologies. No significant differences in changes between the exercise group and the control group were obtained in any of the measured variables, except in patients with idiopathic dilated cardiomyopathy (IDCM), where significant reductions in CRP, ICAM-1, TGF-β and TNF-α levels were observed (p < 0.05 for all). CONCLUSIONS: Measures of CHF severity were significantly correlated with several markers of inflammation. We could not demonstrate over-all anti-inflammatory effect of exercise in this population of CHF patients. However, the etiology of CHF affected the inflammatory profile and the effect of exercise training.