Skeletal Muscle Alterations Are Exacerbated in Heart Failure With Reduced Compared With Preserved Ejection Fraction: Mediated by Circulating Cytokines?
A greater understanding of the different underlying mechanisms between patients with heart failure with reduced (HFrEF) and with preserved (HFpEF) ejection fraction is urgently needed to better direct future treatment. However, although skeletal muscle impairments, potentially mediated by inflammatory cytokines, are common in both HFrEF and HFpEF, the underlying cellular and molecular alterations that exist between groups are yet to be systematically evaluated. The present study, therefore, used established animal models to compare whether alterations in skeletal muscle (limb and respiratory) were different between HFrEF and HFpEF, while further characterizing inflammatory cytokines.



Rats were assigned to (1) HFrEF (ligation of the left coronary artery; n=8); (2) HFpEF (high-salt diet; n=10); (3) control (con: no intervention; n=7). Heart failure was confirmed by echocardiography and invasive measures. Soleus tissue in HFrEF, but not in HFpEF, showed a significant increase in markers of (1) muscle atrophy (ie, MuRF1, calpain, and ubiquitin proteasome); (2) oxidative stress (ie, higher nicotinamide adenine dinucleotide phosphate oxidase but lower antioxidative enzyme activities); (3) mitochondrial impairments (ie, a lower succinate dehydrogenase/lactate dehydrogenase ratio and peroxisome proliferator-activated receptor-γ coactivator-1α expression). The diaphragm remained largely unaffected between groups. Plasma concentrations of circulating cytokines were significantly increased in HFrEF for tumor necrosis factor-α, whereas interleukin-1β and interleukin-12 were higher in HFpEF.



Our findings suggest, for the first time, that skeletal muscle alterations are exacerbated in HFrEF compared with HFpEF, which predominantly reside in limb, rather than in respiratory, muscle. This disparity may be mediated, in part, by the different circulating inflammatory cytokines that were elevated between HFpEF and HFrEF.
From the Department of Cardiology (M.S., T.S.B., S.W., T.F., N.M., A.L., G.S., V.A.) and Department of Cardiac Surgery (M.-T.D.), University of Leipzig, Heart Center, Germany; Department of Circulation and Medical Imaging, Faculty of Medicine, K.G. Jebsen Center of Exercise in Medicine, Norwegian University of Science and Technology, Trondheim, Norway (N.R., U.W.); Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Japan (T.H.); Department of Prevention, Rehabilitation and Sports Medicine, Else Kröner-Fresenius-Zentrum, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany (M.H.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Germany (M.H.).
Martin
M
Seiler
From the Department of Cardiology (M.S., T.S.B., S.W., T.F., N.M., A.L., G.S., V.A.) and Department of Cardiac Surgery (M.-T.D.), University of Leipzig, Heart Center, Germany; Department of Circulation and Medical Imaging, Faculty of Medicine, K.G. Jebsen Center of Exercise in Medicine, Norwegian University of Science and Technology, Trondheim, Norway (N.R., U.W.); Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Japan (T.H.); Department of Prevention, Rehabilitation and Sports Medicine, Else Kröner-Fresenius-Zentrum, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany (M.H.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Germany (M.H.).
T Scott
TS
Bowen
From the Department of Cardiology (M.S., T.S.B., S.W., T.F., N.M., A.L., G.S., V.A.) and Department of Cardiac Surgery (M.-T.D.), University of Leipzig, Heart Center, Germany; Department of Circulation and Medical Imaging, Faculty of Medicine, K.G. Jebsen Center of Exercise in Medicine, Norwegian University of Science and Technology, Trondheim, Norway (N.R., U.W.); Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Japan (T.H.); Department of Prevention, Rehabilitation and Sports Medicine, Else Kröner-Fresenius-Zentrum, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany (M.H.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Germany (M.H.).
Natale
N
Rolim
From the Department of Cardiology (M.S., T.S.B., S.W., T.F., N.M., A.L., G.S., V.A.) and Department of Cardiac Surgery (M.-T.D.), University of Leipzig, Heart Center, Germany; Department of Circulation and Medical Imaging, Faculty of Medicine, K.G. Jebsen Center of Exercise in Medicine, Norwegian University of Science and Technology, Trondheim, Norway (N.R., U.W.); Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Japan (T.H.); Department of Prevention, Rehabilitation and Sports Medicine, Else Kröner-Fresenius-Zentrum, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany (M.H.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Germany (M.H.).
Maja-Theresa
MT
Dieterlen
From the Department of Cardiology (M.S., T.S.B., S.W., T.F., N.M., A.L., G.S., V.A.) and Department of Cardiac Surgery (M.-T.D.), University of Leipzig, Heart Center, Germany; Department of Circulation and Medical Imaging, Faculty of Medicine, K.G. Jebsen Center of Exercise in Medicine, Norwegian University of Science and Technology, Trondheim, Norway (N.R., U.W.); Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Japan (T.H.); Department of Prevention, Rehabilitation and Sports Medicine, Else Kröner-Fresenius-Zentrum, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany (M.H.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Germany (M.H.).
Sarah
S
Werner
From the Department of Cardiology (M.S., T.S.B., S.W., T.F., N.M., A.L., G.S., V.A.) and Department of Cardiac Surgery (M.-T.D.), University of Leipzig, Heart Center, Germany; Department of Circulation and Medical Imaging, Faculty of Medicine, K.G. Jebsen Center of Exercise in Medicine, Norwegian University of Science and Technology, Trondheim, Norway (N.R., U.W.); Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Japan (T.H.); Department of Prevention, Rehabilitation and Sports Medicine, Else Kröner-Fresenius-Zentrum, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany (M.H.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Germany (M.H.).
Tomoya
T
Hoshi
From the Department of Cardiology (M.S., T.S.B., S.W., T.F., N.M., A.L., G.S., V.A.) and Department of Cardiac Surgery (M.-T.D.), University of Leipzig, Heart Center, Germany; Department of Circulation and Medical Imaging, Faculty of Medicine, K.G. Jebsen Center of Exercise in Medicine, Norwegian University of Science and Technology, Trondheim, Norway (N.R., U.W.); Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Japan (T.H.); Department of Prevention, Rehabilitation and Sports Medicine, Else Kröner-Fresenius-Zentrum, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany (M.H.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Germany (M.H.).
Tina
T
Fischer
From the Department of Cardiology (M.S., T.S.B., S.W., T.F., N.M., A.L., G.S., V.A.) and Department of Cardiac Surgery (M.-T.D.), University of Leipzig, Heart Center, Germany; Department of Circulation and Medical Imaging, Faculty of Medicine, K.G. Jebsen Center of Exercise in Medicine, Norwegian University of Science and Technology, Trondheim, Norway (N.R., U.W.); Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Japan (T.H.); Department of Prevention, Rehabilitation and Sports Medicine, Else Kröner-Fresenius-Zentrum, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany (M.H.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Germany (M.H.).
Norman
N
Mangner
From the Department of Cardiology (M.S., T.S.B., S.W., T.F., N.M., A.L., G.S., V.A.) and Department of Cardiac Surgery (M.-T.D.), University of Leipzig, Heart Center, Germany; Department of Circulation and Medical Imaging, Faculty of Medicine, K.G. Jebsen Center of Exercise in Medicine, Norwegian University of Science and Technology, Trondheim, Norway (N.R., U.W.); Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Japan (T.H.); Department of Prevention, Rehabilitation and Sports Medicine, Else Kröner-Fresenius-Zentrum, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany (M.H.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Germany (M.H.).
Axel
A
Linke
From the Department of Cardiology (M.S., T.S.B., S.W., T.F., N.M., A.L., G.S., V.A.) and Department of Cardiac Surgery (M.-T.D.), University of Leipzig, Heart Center, Germany; Department of Circulation and Medical Imaging, Faculty of Medicine, K.G. Jebsen Center of Exercise in Medicine, Norwegian University of Science and Technology, Trondheim, Norway (N.R., U.W.); Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Japan (T.H.); Department of Prevention, Rehabilitation and Sports Medicine, Else Kröner-Fresenius-Zentrum, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany (M.H.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Germany (M.H.).
Gerhard
G
Schuler
From the Department of Cardiology (M.S., T.S.B., S.W., T.F., N.M., A.L., G.S., V.A.) and Department of Cardiac Surgery (M.-T.D.), University of Leipzig, Heart Center, Germany; Department of Circulation and Medical Imaging, Faculty of Medicine, K.G. Jebsen Center of Exercise in Medicine, Norwegian University of Science and Technology, Trondheim, Norway (N.R., U.W.); Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Japan (T.H.); Department of Prevention, Rehabilitation and Sports Medicine, Else Kröner-Fresenius-Zentrum, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany (M.H.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Germany (M.H.).
Martin
M
Halle
From the Department of Cardiology (M.S., T.S.B., S.W., T.F., N.M., A.L., G.S., V.A.) and Department of Cardiac Surgery (M.-T.D.), University of Leipzig, Heart Center, Germany; Department of Circulation and Medical Imaging, Faculty of Medicine, K.G. Jebsen Center of Exercise in Medicine, Norwegian University of Science and Technology, Trondheim, Norway (N.R., U.W.); Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Japan (T.H.); Department of Prevention, Rehabilitation and Sports Medicine, Else Kröner-Fresenius-Zentrum, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany (M.H.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Germany (M.H.).
Ulrik
U
Wisloff
From the Department of Cardiology (M.S., T.S.B., S.W., T.F., N.M., A.L., G.S., V.A.) and Department of Cardiac Surgery (M.-T.D.), University of Leipzig, Heart Center, Germany; Department of Circulation and Medical Imaging, Faculty of Medicine, K.G. Jebsen Center of Exercise in Medicine, Norwegian University of Science and Technology, Trondheim, Norway (N.R., U.W.); Cardiovascular Division, Faculty of Medicine, University of Tsukuba, Japan (T.H.); Department of Prevention, Rehabilitation and Sports Medicine, Else Kröner-Fresenius-Zentrum, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany (M.H.); and DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Germany (M.H.). adav@medizin.uni-leipzig.de.
Volker
V
Adams
D000818:Animals; D016207:Cytokines / Q000097:blood*; D003964:Diaphragm / Q000378:metabolism; D004195:Disease Models, Animal; D006333:Heart Failure / Q000097:blood* / Q000473:pathology / Q000503:physiopathology; D018836:Inflammation Mediators / Q000097:blood*; D018664:Interleukin-12 / Q000097:blood; D053583:Interleukin-1beta / Q000097:blood; D008931:Mitochondria, Muscle / Q000378:metabolism; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009133:Muscular Atrophy / Q000097:blood / Q000473:pathology; D018384:Oxidative Stress; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D013318:Stroke Volume; D014409:Tumor Necrosis Factor-alpha / Q000097:blood; D015854:Up-Regulation; D016277:Ventricular Function, Left
D016207:Cytokines; C000594089:IL1B protein, rat; D018836:Inflammation Mediators; D053583:Interleukin-1beta; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12
diaphragm; heart failure; heart failure, diastolic; muscles; oxidative stress; proteasome endopeptidase complex