Skeletal muscle alterations in tachycardia-induced heart failure are linked to deficient natriuretic peptide signalling and are attenuated by RAS-/NEP-inhibition

Autoři: Alexander Dietl aff001;  Ingrid Winkel aff002;  Gabriela Pietrzyk aff001;  Michael Paulus aff001;  Astrid Bruckmann aff003;  Josef A. Schröder aff004;  Samuel Sossalla aff001;  Andreas Luchner aff001;  Lars S. Maier aff001;  Christoph Birner aff001
Působiště autorů: Department of Internal Medicine II, University Hospital Regensburg, Regensburg, Germany aff001;  Institute of Pathology, University of Regensburg, Regensburg, Germany aff002;  Department of Biochemistry I, University of Regensburg, Regensburg, Germany aff003;  Electron Microscopy Core Facility (Emeritus), Institute for Pathology, University Hospital Regensburg, Regensburg, Germany aff004;  Klinik fuer Kardiologie, Krankenhaus der Barmherzigen Brueder, Regensburg, Germany aff005;  Department of Internal Medicine I, Klinikum St. Marien, Amberg, Germany aff006
Vyšlo v časopise: PLoS ONE 14(12)
Kategorie: Research Article
prolekare.web.journal.doi_sk: 10.1371/journal.pone.0225937



Heart failure induced cachexia is highly prevalent. Insights into disease progression are lacking.


Early state of left ventricular dysfunction (ELVD) and symptomatic systolic heart failure (HF) were both induced in rabbits by tachypacing. Tissue of limb muscle (LM) was subjected to histologic assessment. For unbiased characterisation of early and late myopathy, a proteomic approach followed by computational pathway-analyses was performed and combined with pathway-focused gene expression analyses. Specimen of thoracic diaphragm (TD) served as control for inactivity-induced skeletal muscle alterations. In a subsequent study, inhibition of the renin-angiotensin-system and neprilysin (RAS-/NEP) was compared to placebo.


HF was accompanied by loss of protein content (8.7±0.4% vs. 7.0±0.5%, mean±SEM, control vs. HF, p<0.01) and a slow-to-fast fibre type switch, establishing hallmarks of cachexia. In ELVD, the enzymatic set-up of LM and TD shifted to a catabolic state. A disturbed malate-aspartate shuttle went well with increased enzymes of glycolysis, forming the enzymatic basis for enforced anoxic energy regeneration. The histological findings and the pathway analysis of metabolic results drew the picture of suppressed PGC-1α signalling, linked to the natriuretic peptide system. In HF, natriuretic peptide signalling was desensitised, as confirmed by an increase in the ratio of serum BNP to tissue cGMP (57.0±18.6pg/ml/nM/ml vs. 165.8±16.76pg/ml/nM/ml, p<0.05) and a reduced expression of natriuretic peptide receptor-A. In HF, combined RAS-/NEP-inhibition prevented from loss in protein content (8.7±0.3% vs. 6.0±0.6% vs. 8.3±0.9%, Baseline vs. HF-Placebo vs. HF-RAS/NEP, p<0.05 Baseline vs. HF-Placebo, p = 0.7 Baseline vs. HF-RAS/NEP).


Tachypacing-induced heart failure entails a generalised myopathy, preceding systolic dysfunction. The characterisation of “pre-cachectic” state and its progression is feasible. Early enzymatic alterations of LM depict a catabolic state, rendering LM prone to futile substrate metabolism. A combined RAS-/NEP-inhibition ameliorates cardiac-induced myopathy independent of systolic function, which could be linked to stabilised natriuretic peptide/cGMP/PGC-1α signalling.

Klíčová slova:

Cytosol – Enzyme metabolism – Heart failure – Mitochondria – Rabbits – Signal peptides – Skeletal muscles – Natriuretic peptide


1. Braunwald E. The war against heart failure: the Lancet lecture. Lancet. 2015;385: 812–824. doi: 10.1016/S0140-6736(14)61889-4 25467564

2. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur J Heart Fail. 2016;18: 891–975. doi: 10.1002/ejhf.592 27207191

3. Dietl A, Prieschenk C, Eckert F, Birner C, Luchner A, Maier LS, et al. 3D vena contracta area after MitraClip procedure: precise quantification of residual mitral regurgitation and identification of prognostic information. Cardiovasc Ultrasound. 2018;16: 1. doi: 10.1186/s12947-017-0120-9 29310672

4. Maack C, Eschenhagen T, Hamdani N, Heinzel FR, Lyon AR, Manstein DJ, et al. Treatments targeting inotropy. Eur Heart J. 2018; doi: 10.1093/eurheartj/ehy600 30295807

5. von Haehling S, Ebner N, dos Santos MR, Springer J, Anker SD. Muscle wasting and cachexia in heart failure: mechanisms and therapies. Nat Rev Cardiol. 2017;14: 323–341. doi: 10.1038/nrcardio.2017.51 28436486

6. Anker SD, Ponikowski P, Varney S, Chua TP, Clark AL, Webb-Peploe KM, et al. Wasting as independent risk factor for mortality in chronic heart failure. Lancet. 1997;349: 1050–1053. doi: 10.1016/S0140-6736(96)07015-8 9107242

7. Muscaritoli M, Anker SD, Argilés J, Aversa Z, Bauer JM, Biolo G, et al. Consensus definition of sarcopenia, cachexia and pre-cachexia: joint document elaborated by Special Interest Groups (SIG) “cachexia-anorexia in chronic wasting diseases”; and “nutrition in geriatrics.” Clin Nutr. 2010;29: 154–9. doi: 10.1016/j.clnu.2009.12.004 20060626

8. Ishida J, Saitoh M, Doehner W, von Haehling S, Anker M, Anker SD, et al. Animal models of cachexia and sarcopenia in chronic illness: Cardiac function, body composition changes and therapeutic results. Int J Cardiol. 2017;238: 12–18. doi: 10.1016/j.ijcard.2017.03.154 28476513

9. Dietl A, Winkel I, Deutzmann R, Schröder J, Hupf J, Riegger G, et al. Interatrial differences of basal molecular set-up and changes in tachycardia-induced heart failure-a proteomic profiling study. Eur J Heart Fail. 2014;16: 835–845. doi: 10.1002/ejhf.122 25045083

10. Birner C, Dietl A, Deutzmann R, Schröder J, Schmid P, Jungbauer C, et al. Proteomic profiling implies mitochondrial dysfunction in tachycardia-induced heart failure. J Card Fail. 2012;18: 660–673. doi: 10.1016/j.cardfail.2012.06.418 22858083

11. Pan L, Yang H, Tang W, Xu C, Chen S, Meng Z, et al. Pathway-focused PCR array profiling of CAL-27 cell with over-expressed ZNF750. Oncotarget. 2018;9: 566–575. doi: 10.18632/oncotarget.23075 29416636

12. Grois L, Hupf J, Reinders J, Schröder J, Dietl A, Schmid PM, et al. Combined Inhibition of the Renin-Angiotensin System and Neprilysin Positively Influences Complex Mitochondrial Adaptations in Progressive Experimental Heart Failure. Lesnefsky EJ, editor. PLoS One. 2017;12: e0169743. doi: 10.1371/journal.pone.0169743 28076404

13. Ohlendieck K. Comparative DIGE Proteomics. Methods in molecular biology (Clifton, NJ). 2018. pp. 17–24. doi: 10.1007/978-1-4939-7268-5_2 29019121

14. Engeli S, Birkenfeld AL, Badin P-M, Bourlier V, Louche K, Viguerie N, et al. Natriuretic peptides enhance the oxidative capacity of human skeletal muscle. J Clin Invest. 2012;122: 4675–4679. doi: 10.1172/JCI64526 23114600

15. Díez J. Chronic heart failure as a state of reduced effectiveness of the natriuretic peptide system: implications for therapy. Eur J Heart Fail. 2017;19: 167–176. doi: 10.1002/ejhf.656 27766748

16. Chen HH, Lainchbury JG, Harty GJ, Burnett JC. Maximizing the natriuretic peptide system in experimental heart failure: subcutaneous brain natriuretic peptide and acute vasopeptidase inhibition. Circulation. 2002;105: 999–1003. doi: 10.1161/hc0802.104282 11864932

17. Wong V, Szeto L, Uffelman K, Fantus IG, Lewis GF. Enhancement of muscle glucose uptake by the vasopeptidase inhibitor, omapatrilat, is independent of insulin signaling and the AMP kinase pathway. J Endocrinol. 2006;190: 441–450. doi: 10.1677/joe.1.06396 16899577

18. Ferrario CM, Averill DB, Brosnihan KB, Chappell MC, Iskandar SS, Dean RH, et al. Vasopeptidase inhibition and Ang-(1–7) in the spontaneously hypertensive rat. Kidney Int. 2002;62: 1349–57. doi: 10.1111/j.1523-1755.2002.kid559.x 12234305

19. Rodriguez-Gomez I, Wangensteen R, Atucha NM, O’Valle F, Del Moral RG, Garcia-Estañ J, et al. Effects of omapatrilat on blood pressure and renal injury in L-NAME and L-NAME plus DOCA-treated rats. Am J Hypertens. 2003;16: 33–38. doi: 10.1016/s0895-7061(02)03144-8 12517680

20. Ying L, Flamant M, Vandermeersch S, Boffa J-J, Chatziantoniou C, Dussaule J-C, et al. Renal effects of omapatrilat and captopril in salt-loaded, nitric oxide-deficient rats. Hypertens (Dallas, Tex 1979). 2003;42: 937–44. doi: 10.1161/01.HYP.0000099240.89890.94 14569001

21. Martinic G. A technique for intragastric gavage of radiolabeled liquid cholesterol in rabbits (Oryctolagus cuniculus) using a pediatric feeding tube. Lab Animal. 2008. pp. 323–328. doi: 10.1038/laban0708-323 18568011

22. Rouleau JL, Pfeffer MA, Stewart DJ, Isaac D, Sestier F, Kerut EK, et al. Comparison of vasopeptidase inhibitor, omapatrilat, and lisinopril on exercise tolerance and morbidity in patients with heart failure: IMPRESS randomised trial. Lancet (London, England). 2000;356: 615–20. doi: 10.1016/s0140-6736(00)02602-7

23. Birner C, Ulucan C, Bratfisch M, Götz T, Dietl A, Schweda F, et al. Antihypertrophic effects of combined inhibition of the renin-angiotensin system (RAS) and neutral endopeptidase (NEP) in progressive, tachycardia-induced experimental heart failure. Naunyn Schmiedebergs Arch Pharmacol. 2012;385: 1117–1125. doi: 10.1007/s00210-012-0791-6 22895639

24. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for Cardiac Chamber Quantification by Echocardiography in Adults: An Update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Hear J—Cardiovasc Imaging. 2015;16: 233–271. doi: 10.1093/ehjci/jev014 25712077

25. Ramos SR, Pieles G, Hui W, Ishii R, Slorach C, Friedberg MK. Comprehensive echocardiographic assessment of biventricular function in the rabbit, animal model in cardiovascular research: feasibility and normal values. Int J Cardiovasc Imaging. 2018;34: 367–375. doi: 10.1007/s10554-017-1238-4 28840383

26. Meng H, Janssen PML, Grange RW, Yang L, Beggs AH, Swanson LC, et al. Tissue triage and freezing for models of skeletal muscle disease. J Vis Exp. 2014; doi: 10.3791/51586 25078247

27. Guth L, Samaha FJ. Procedure for the histochemical demonstration of actomyosin ATPase. Exp Neurol. 1970;28: 365–7. Available:

28. Birner C, Hierl S, Dietl A, Hupf J, Jungbauer C, Schmid PM, et al. Experimental Heart Failure Induces Alterations of the Lung Proteome—Insight into Molecular Mechanisms. Cell Physiol Biochem. 2014;33: 692–704. doi: 10.1159/000358645 24643085

29. The Gene Ontology Consortium. Expansion of the Gene Ontology knowledgebase and resources. Nucleic Acids Res. 2017;45: D331–D338. doi: 10.1093/nar/gkw1108 27899567

30. Bateman A, Martin MJ, O’Donovan C, Magrane M, Alpi E, Antunes R, et al. UniProt: the universal protein knowledgebase. Nucleic Acids Res. 2017;45: D158–D169. doi: 10.1093/nar/gkw1099 27899622

31. Craig DB, Kannan S, Dombkowski AA. Augmented annotation and orthologue analysis for Oryctolagus cuniculus: Better Bunny. BMC Bioinformatics. 2012;13: 84. doi: 10.1186/1471-2105-13-84 22568790

32. Mi H, Huang X, Muruganujan A, Tang H, Mills C, Kang D, et al. PANTHER version 11: expanded annotation data from Gene Ontology and Reactome pathways, and data analysis tool enhancements. Nucleic Acids Res. 2017;45: D183–D189. doi: 10.1093/nar/gkw1138 27899595

33. Gürtler A, Kunz N, Gomolka M, Hornhardt S, Friedl AA, McDonald K, et al. Stain-Free technology as a normalization tool in Western blot analysis. Anal Biochem. 2013;433: 105–111. doi: 10.1016/j.ab.2012.10.010 23085117

34. Kramer KA, Oglesbee D, Hartman SJ, Huey J, Anderson B, Magera MJ, et al. Automated spectrophotometric analysis of mitochondrial respiratory chain complex enzyme activities in cultured skin fibroblasts. Clin Chem. 2005;51: 2110–6. doi: 10.1373/clinchem.2005.050146 16141288

35. Spinazzi M, Casarin A, Pertegato V, Salviati L, Angelini C. Assessment of mitochondrial respiratory chain enzymatic activities on tissues and cultured cells. Nat Protoc. 2012;7: 1235–46. doi: 10.1038/nprot.2012.058 22653162

36. Srere P. Citrate synthase. In: Lowenstein J, editor. Methods in enzymology, citric acid cycle. New York: Academic Press; 1973. pp. 3–11.

37. Apple FS, Panteghini M, Ravkilde J, Mair J, Wu AHB, Tate J, et al. Quality Specifications for B-Type Natriuretic Peptide Assays. Clin Chem. 2005;51: 486–493. doi: 10.1373/clinchem.2004.044594 15738513

38. Fieller EC. The Biological Standardization of Insulin. Suppl to J R Stat Soc. 1940;7: 1. doi: 10.2307/2983630

39. GraphPad QuickCalcs: error propagation calculator [Internet]. [cited 15 Oct 2019].

40. Smith SM. Strategies for the Purification of Membrane Proteins. Methods in molecular biology (Clifton, NJ). 2017. pp. 389–400.

41. Doehner W, Frenneaux M, Anker SD. Metabolic impairment in heart failure: the myocardial and systemic perspective. J Am Coll Cardiol. 2014;64: 1388–400. doi: 10.1016/j.jacc.2014.04.083 25257642

42. Heineke J, Auger-Messier M, Xu J, Sargent M, York A, Welle S, et al. Genetic Deletion of Myostatin From the Heart Prevents Skeletal Muscle Atrophy in Heart Failure. Circulation. 2010;121: 419–425. doi: 10.1161/CIRCULATIONAHA.109.882068 20065166

43. Holecek M. Muscle wasting in animal models of severe illness. Int J Exp Pathol. 2012;93: 157–71. doi: 10.1111/j.1365-2613.2012.00812.x 22564195

44. Mangner N, Weikert B, Bowen TS, Sandri M, Höllriegel R, Erbs S, et al. Skeletal muscle alterations in chronic heart failure: differential effects on quadriceps and diaphragm. J Cachexia Sarcopenia Muscle. 2015;6: 381–390. doi: 10.1002/jcsm.12034 26674018

45. Shinbane JS, Wood MA, Jensen DN, Ellenbogen KA, Fitzpatrick AP, Scheinman MM. Tachycardia-induced cardiomyopathy: A review of animal models and clinical studies. Journal of the American College of Cardiology. Elsevier USA; 1997. pp. 709–715. doi: 10.1016/S0735-1097(96)00592-X

46. Sossalla S, Vollmann D. Arrhythmia-induced cardiomyopathy. Dtsch Aerzteblatt Online. 2018;115: 335–341. doi: 10.3238/arztebl.2018.0335 29875055

47. Fredersdorf S, Fenzl C, Jungbauer C, Weber S, von Bary C, Dietl A, et al. Long-term outcomes and predictors of recurrence after pulmonary vein isolation with multielectrode ablation catheter in patients with atrial fibrillation. J Cardiovasc Med. 2018;19: 148–154. doi: 10.2459/JCM.0000000000000631 29432401

48. Marrouche NF, Brachmann J, Andresen D, Siebels J, Boersma L, Jordaens L, et al. Catheter Ablation for Atrial Fibrillation with Heart Failure. N Engl J Med. 2018;378: 417–427. doi: 10.1056/NEJMoa1707855 29385358

49. Braunwald E. Heart Failure. JACC Hear Fail. 2013;1: 1–20. doi: 10.1016/j.jchf.2012.10.002 24621794

50. Tiller D, Russ M, Greiser KH, Nuding S, Ebelt H, Kluttig A, et al. Prevalence of Symptomatic Heart Failure with Reduced and with Normal Ejection Fraction in an Elderly General Population–The CARLA Study. Bauer WR, editor. PLoS One. 2013;8: e59225. doi: 10.1371/journal.pone.0059225 23555000

51. Redfield MM, Jacobsen SJ, Burnett JC, Mahoney DW, Bailey KR, Rodeheffer RJ. Burden of systolic and diastolic ventricular dysfunction in the community: appreciating the scope of the heart failure epidemic. JAMA. 2003;289. doi: 10.1001/jama.289.2.194 12517230

52. McMurray JJV, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371: 993–1004. doi: 10.1056/NEJMoa1409077 25176015

53. Birner C, Ulucan C, Bratfisch M, Götz T, Dietl A, Schweda F, et al. Antihypertrophic effects of combined inhibition of the renin-angiotensin system (RAS) and neutral endopeptidase (NEP) in progressive, tachycardia-induced experimental heart failure. Naunyn Schmiedebergs Arch Pharmacol. 2012;385: 1117–25. doi: 10.1007/s00210-012-0791-6 22895639

54. Birner CM, Ulucan C, Fredersdorf S, Rihm M, Löwel H, Stritzke J, et al. Head-to-head comparison of BNP and IL-6 as markers of clinical and experimental heart failure: Superiority of BNP. Cytokine. 2007;40: 89–97. doi: 10.1016/j.cyto.2007.08.009 17920926

55. Elsner D, Riegger GAJ. Experimental heart failure produced by rapid ventricular pacing in the dog. J Card Fail. 1995;1: 229–247. doi: 10.1016/1071-9164(95)90029-2 9420656

56. Mancini DM, Coyle E, Coggan A, Beltz J, Ferraro N, Montain S, et al. Contribution of intrinsic skeletal muscle changes to 31P NMR skeletal muscle metabolic abnormalities in patients with chronic heart failure. Circulation. 1989;80: 1338–46. Available:

57. Melenovsky V, Hlavata K, Sedivy P, Dezortova M, Borlaug BA, Petrak J, et al. Skeletal Muscle Abnormalities and Iron Deficiency in Chronic Heart Failure. Circ Hear Fail. 2018;11: e004800. doi: 10.1161/CIRCHEARTFAILURE.117.004800 30354361

58. Shrikrishna D, Patel M, Tanner RJ, Seymour JM, Connolly BA, Puthucheary ZA, et al. Quadriceps wasting and physical inactivity in patients with COPD. Eur Respir J. 2012;40: 1115–22. doi: 10.1183/09031936.00170111 22362854

59. Cho Y, Ross RS. A mini review: Proteomics approaches to understand disused vs. exercised human skeletal muscle. Physiol Genomics. 2018;50: 746–757. doi: 10.1152/physiolgenomics.00043.2018 29958080

60. Moriggi M, Vasso M, Fania C, Capitanio D, Bonifacio G, Salanova M, et al. Long term bed rest with and without vibration exercise countermeasures: Effects on human muscle protein dysregulation. Proteomics. 2010;10: 3756–3774. doi: 10.1002/pmic.200900817 20957755

61. Georgiadou P, Adamopoulos S. Skeletal Muscle Abnormalities in Chronic Heart Failure. Curr Heart Fail Rep. 2012;9: 128–132. doi: 10.1007/s11897-012-0090-z 22430147

62. von Haehling S. Casting the net broader to confirm our imaginations: the long road to treating wasting disorders. J Cachexia Sarcopenia Muscle. 2017;8: 870–880. doi: 10.1002/jcsm.12256 29168628

63. Habedank D, Meyer FJ, Hetzer R, Anker SD, Ewert R. Relation of respiratory muscle strength, cachexia and survival in severe chronic heart failure. J Cachexia Sarcopenia Muscle. 2013;4: 277–85. doi: 10.1007/s13539-013-0109-7 23794292

64. Hamazaki N, Masuda T, Kamiya K, Matsuzawa R, Nozaki K, Maekawa E, et al. Respiratory muscle weakness increases dead-space ventilation ratio aggravating ventilation-perfusion mismatch during exercise in patients with chronic heart failure. Respirology. 2019;24: 154–161. doi: 10.1111/resp.13432 30426601

65. Anker SD, Chua TP, Ponikowski P, Harrington D, Swan JW, Kox WJ, et al. Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia. Circulation. 1997;96: 526–34. Available:

66. Kane DA. Lactate oxidation at the mitochondria: a lactate-malate-aspartate shuttle at work. Front Neurosci. 2014;8: 366. doi: 10.3389/fnins.2014.00366 25505376

67. Robergs RA, Ghiasvand F, Parker D. Biochemistry of exercise-induced metabolic acidosis. Am J Physiol Integr Comp Physiol. 2004;287: R502–R516. doi: 10.1152/ajpregu.00114.2004 15308499

68. Feridooni HA, Kane AE, Ayaz O, Boroumandi A, Polidovitch N, Tsushima RG, et al. The impact of age and frailty on ventricular structure and function in C57BL/6J mice. J Physiol. 2017;595: 3721–3742. doi: 10.1113/JP274134 28502095

69. Massie B, Conway M, Yonge R, Frostick S, Ledingham J, Sleight P, et al. Skeletal muscle metabolism in patients with congestive heart failure: relation to clinical severity and blood flow. Circulation. 1987;76: 1009–19. Available:

70. Huckabee WE, Judson WE. The Role of Anaerobic Metabolism in the Performance of Mild Muscular Work. I. Relationship to Oxygen Consumption and Cardiac Output, and the Effect of Congestive Heart Failure1. J Clin Invest. 1958;37: 1577–1592. doi: 10.1172/JCI103751 13587668

71. Dietl A, Maack C. Targeting Mitochondrial Calcium Handling and Reactive Oxygen Species in Heart Failure. Curr Heart Fail Rep. 2017;14: 338–349. doi: 10.1007/s11897-017-0347-7 28656516

72. Wang J, Li Z, Chen J, Zhao H, Luo L, Chen C, et al. Metabolomic identification of diagnostic plasma biomarkers in humans with chronic heart failure. Mol Biosyst. 2013;9: 2618. doi: 10.1039/c3mb70227h 23959290

73. Zymliński R, Biegus J, Sokolski M, Siwołowski P, Nawrocka-Millward S, Todd J, et al. Increased blood lactate is prevalent and identifies poor prognosis in patients with acute heart failure without overt peripheral hypoperfusion. Eur J Heart Fail. 2018;20: 1011–1018. doi: 10.1002/ejhf.1156 29431284

74. Vaughan VC, Martin P, Lewandowski PA. Cancer cachexia: impact, mechanisms and emerging treatments. J Cachexia Sarcopenia Muscle. 2013;4: 95–109. doi: 10.1007/s13539-012-0087-1 23097000

75. Tisdale MJ. Mechanisms of cancer cachexia. Physiol Rev. 2009;89: 381–410. doi: 10.1152/physrev.00016.2008 19342610

76. Holroyde CP, Skutches CL, Boden G, Reichard GA. Glucose metabolism in cachectic patients with colorectal cancer. Cancer Res. 1984;44: 5910–3. Available:

77. Porporato PE. Understanding cachexia as a cancer metabolism syndrome. Oncogenesis. 2016;5: e200–e200. doi: 10.1038/oncsis.2016.3 26900952

78. Chan MC, Arany Z. The many roles of PGC-1α in muscle—recent developments. Metabolism. 2014;63: 441–51. doi: 10.1016/j.metabol.2014.01.006 24559845

79. Lin J, Wu H, Tarr PT, Zhang C-Y, Wu Z, Boss O, et al. Transcriptional co-activator PGC-1α drives the formation of slow-twitch muscle fibres. Nature. 2002;418: 797–801. doi: 10.1038/nature00904 12181572

80. Handschin C, Chin S, Li P, Liu F, Maratos-Flier E, LeBrasseur NK, et al. Skeletal Muscle Fiber-type Switching, Exercise Intolerance, and Myopathy in PGC-1α Muscle-specific Knock-out Animals. J Biol Chem. 2007;282: 30014–30021. doi: 10.1074/jbc.M704817200 17702743

81. Wende AR, Schaeffer PJ, Parker GJ, Zechner C, Han D-H, Chen MM, et al. A Role for the Transcriptional Coactivator PGC-1α in Muscle Refueling. J Biol Chem. 2007;282: 36642–36651. doi: 10.1074/jbc.M707006200 17932032

82. Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, et al. Mechanisms Controlling Mitochondrial Biogenesis and Respiration through the Thermogenic Coactivator PGC-1. Cell. 1999;98: 115–124. doi: 10.1016/S0092-8674(00)80611-X 10412986

83. Dietl A, Stark K, Zimmermann ME, Meisinger C, Schunkert H, Birner C, et al. NT-proBNP predicts cardiovascular death in the general population independent of left ventricular mass and function: Insights from a large population-based study with long-term follow-up. PLoS One. 2016;11: e0164060. doi: 10.1371/journal.pone.0164060 27711172

84. Lourenço P, Araújo JP, Azevedo A, Ferreira A, Bettencourt P. The cyclic guanosine monophosphate/B-type natriuretic peptide ratio and mortality in advanced heart failure. Eur J Heart Fail. 2009;11: 185–90. doi: 10.1093/eurjhf/hfn037 19168517

85. McClean DR, Ikram H, Mehta S, Heywood JT, Rousseau MF, Niederman AL, et al. Vasopeptidase inhibition with omapatrilat in chronic heart failure: acute and long-term hemodynamic and neurohumoral effects. J Am Coll Cardiol. 2002;39: 2034–41. Available:

86. Kobalava Z, Kotovskaya Y, Averkov O, Pavlikova E, Moiseev V, Albrecht D, et al. Pharmacodynamic and Pharmacokinetic Profiles of Sacubitril/Valsartan (LCZ696) in Patients with Heart Failure and Reduced Ejection Fraction. Cardiovasc Ther. 2016;34: 191–198. doi: 10.1111/1755-5922.12183 26990595

87. Chen HH, Schirger JA, Cataliotti A, Burnett JC. Intact acute cardiorenal and humoral responsiveness following chronic subcutaneous administration of the cardiac peptide BNP in experimental heart failure. Eur J Heart Fail. 2006;8: 681–6. doi: 10.1016/j.ejheart.2005.12.005 16459135

88. Singh G, Kuc RE, Maguire JJ, Fidock M, Davenport AP. Novel snake venom ligand dendroaspis natriuretic peptide is selective for natriuretic peptide receptor-A in human heart: downregulation of natriuretic peptide receptor-A in heart failure. Circ Res. 2006;99: 183–90. doi: 10.1161/01.RES.0000232322.06633.d3 16778132

89. Müller D, Cortes-Dericks L, Budnik LT, Brunswig-Spickenheier B, Pancratius M, Speth RC, et al. Homologous and lysophosphatidic acid-induced desensitization of the atrial natriuretic peptide receptor, guanylyl cyclase-A, in MA-10 leydig cells. Endocrinology. 2006;147: 2974–85. doi: 10.1210/en.2006-0092 16527839

90. Schröter J, Zahedi RP, Hartmann M, Gassner B, Gazinski A, Waschke J, et al. Homologous desensitization of guanylyl cyclase A, the receptor for atrial natriuretic peptide, is associated with a complex phosphorylation pattern. FEBS J. 2010;277: 2440–53. doi: 10.1111/j.1742-4658.2010.07658.x 20456499

91. Forfia PR, Lee M, Tunin RS, Mahmud M, Champion HC, Kass DA. Acute phosphodiesterase 5 inhibition mimics hemodynamic effects of B-type natriuretic peptide and potentiates B-type natriuretic peptide effects in failing but not normal canine heart. J Am Coll Cardiol. 2007;49: 1079–88. doi: 10.1016/j.jacc.2006.08.066 17349888

92. Packer M, Califf RM, Konstam MA, Krum H, McMurray JJ, Rouleau J-L, et al. Comparison of omapatrilat and enalapril in patients with chronic heart failure: the Omapatrilat Versus Enalapril Randomized Trial of Utility in Reducing Events (OVERTURE). Circulation. 2002;106: 920–6. Available:

93. Volpe M, Rubattu S, Burnett J. Natriuretic peptides in cardiovascular diseases: current use and perspectives. Eur Heart J. 2014;35: 419–25. doi: 10.1093/eurheartj/eht466 24227810

94. Garnier A, Fortin D, Zoll J, N’Guessan B, Mettauer B, Lampert E, et al. Coordinated changes in mitochondrial function and biogenesis in healthy and diseased human skeletal muscle. FASEB J. 2005;19: 43–52. doi: 10.1096/fj.04-2173com 15629894

95. Baar K, Wende AR, Jones TE, Marison M, Nolte LA, Chen M, et al. Adaptations of skeletal muscle to exercise: rapid increase in the transcriptional coactivator PGC-1. FASEB J. 2002;16: 1879–1886. doi: 10.1096/fj.02-0367com 12468452

96. Hegde SM, Claggett B, Shah AM, Lewis EF, Anand I, Shah SJ, et al. Physical Activity and Prognosis in the TOPCAT Trial (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist). Circulation. 2017;136: 982–992. doi: 10.1161/CIRCULATIONAHA.117.028002 28637881

97. Omar W, Pandey A, Haykowsky MJ, Berry JD, Lavie CJ. The Evolving Role of Cardiorespiratory Fitness and Exercise in Prevention and Management of Heart Failure. Curr Heart Fail Rep. 2018;15: 75–80. doi: 10.1007/s11897-018-0382-z 29520706

98. Vorderwinkler KP, Artner-Dworzak E, Jakob G, Mair J, Diensti F, Pichler M, et al. Release of cyclic guanosine monophosphate evaluated as a diagnostic tool in cardiac diseases. Clin Chem. 1991;37: 186–90. Available:

99. Lee DI, Zhu G, Sasaki T, Cho G-S, Hamdani N, Holewinski R, et al. Phosphodiesterase 9A controls nitric-oxide-independent cGMP and hypertrophic heart disease. Nature. 2015;519: 472–476. doi: 10.1038/nature14332 25799991

100. Hegde LG, Yu C, Renner T, Thibodeaux H, Armstrong SR, Park T, et al. Concomitant Angiotensin AT1 Receptor Antagonism and Neprilysin Inhibition Produces Omapatrilat-like Antihypertensive Effects Without Promoting Tracheal Plasma Extravasation in the Rat. J Cardiovasc Pharmacol. 2011;57: 495–504. doi: 10.1097/FJC.0b013e318210fc7e 21297495

101. Margulies KB, Perrella MA, McKinley LJ, Burnett JC. Angiotensin inhibition potentiates the renal responses to neutral endopeptidase inhibition in dogs with congestive heart failure. J Clin Invest. 1991;88: 1636–42. doi: 10.1172/JCI115477 1658047

102. Menendez JT. The Mechanism of Action of LCZ696. Card Fail Rev. 2016;2: 40–46. doi: 10.15420/cfr.2016:1:1 28785451

103. Singh JSS, Burrell LM, Cherif M, Squire IB, Clark AL, Lang CC. Sacubitril/valsartan: beyond natriuretic peptides. Heart. 2017;103: 1569–1577. doi: 10.1136/heartjnl-2017-311295 28689178

Článok vyšiel v časopise


2019 Číslo 12