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Unveiling the role of exercise training in targeting the inflammatory paradigm of heart failure with preserved ejection fraction: a narrative review

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Abstract

Heart failure with preserved ejection fraction (HFpEF) is currently lacking an effective pharmacological treatment with impact on major outcomes such as hospitalization and mortality. Exercise training (EXT) is recognized as an important nonpharmacological tool, capable of improving exercise capacity and quality of life, and has even been associated with a reduction in hospitalization and cardiovascular mortality risk. However, this positive impact largely lacks a physiological explanation. The aim of this narrative review was to provide an overview of the available data supporting the hypothesis that the beneficial role of EXT in HFpEF might be due to its effects on targeting the inflammatory paradigm described for this disease. A comprehensive literature search was conducted using the PubMed-NCBI database. We reviewed the effects of EXT throughout each step of the pathophysiological pathway leading to HFpEF and found clinical and/or preclinical evidence supporting the reduction of systemic inflammation, endothelial dysfunction, microvascular rarefaction, and myocardial stiffness. We also highlighted some gaps in the knowledge or topics that deserve further clarification in future studies. In conclusion, despite the scarcity of clinical studies in this population, there is compelling evidence suggesting that EXT modulates crucial aspects of the inflammatory pathway described for HFpEF and future investigation on cellular and molecular mechanisms are encouraged.

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References

  1. Westermann D, Kasner M, Steendijk P, Spillmann F, Riad A, Weitmann K, Hoffmann W, Poller W, Pauschinger M, Schultheiss HP, Tschope C (2008) Role of left ventricular stiffness in heart failure with normal ejection fraction. Circulation 117(16):2051–2060. https://doi.org/10.1161/circulationaha.107.716886

    Article  PubMed  Google Scholar 

  2. Zile MR, Baicu CF, Gaasch WH (2004) Diastolic heart failure—abnormalities in active relaxation and passive stiffness of the left ventricle. N Engl J Med 350(19):1953–1959. https://doi.org/10.1056/NEJMoa032566

    Article  PubMed  CAS  Google Scholar 

  3. Pieske B, Tschope C, de Boer RA, Fraser AG, Anker SD, Donal E, Edelmann F, Fu M, Guazzi M, Lam CSP, Lancellotti P, Melenovsky V, Morris DA, Nagel E, Pieske-Kraigher E, Ponikowski P, Solomon SD, Vasan RS, Rutten FH, Voors AA, Ruschitzka F, Paulus WJ, Seferovic P, Filippatos G (2020) How to diagnose heart failure with preserved ejection fraction: the HFA-PEFF diagnostic algorithm: a consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). Eur J Heart Fail. https://doi.org/10.1002/ejhf.1741

    Article  PubMed  Google Scholar 

  4. Parikh KS, Sharma K, Fiuzat M, Surks HK, George JT, Honarpour N, Depre C, Desvigne-Nickens P, Nkulikiyinka R, Lewis GD, Gomberg-Maitland M, O’Connor CM, Stockbridge N, Califf RM, Konstam MA, Januzzi JL Jr, Solomon SD, Borlaug BA, Shah SJ, Redfield MM, Felker GM (2018) Heart failure with preserved ejection fraction expert panel report: current controversies and implications for clinical trials. JACC Heart failure 6(8):619–632. https://doi.org/10.1016/j.jchf.2018.06.008

    Article  PubMed  Google Scholar 

  5. Paulus WJ, Tschope C (2013) A novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation. J Am Coll Cardiol 62(4):263–271. https://doi.org/10.1016/j.jacc.2013.02.092

    Article  PubMed  Google Scholar 

  6. Sharma K, Kass DA (2014) Heart failure with preserved ejection fraction: mechanisms, clinical features, and therapies. Circ Res 115(1):79–96. https://doi.org/10.1161/circresaha.115.302922

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. U.S. National Library of Medicine CG Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction (EMPEROR-Preserved). https://clinicaltrials.gov/ct2/show/NCT03057951. Accessed April 24, 2020

  8. Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JGF, Coats AJS, Falk V, Gonzalez-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GMC, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P (2016) 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 37(27):2129–2200. https://doi.org/10.1093/eurheartj/ehw128

    Article  PubMed  Google Scholar 

  9. Dieberg G, Ismail H, Giallauria F, Smart NA (2015) Clinical outcomes and cardiovascular responses to exercise training in heart failure patients with preserved ejection fraction: a systematic review and meta-analysis. J Appl Physiol 119(6):726–733. https://doi.org/10.1152/japplphysiol.00904.2014

    Article  PubMed  CAS  Google Scholar 

  10. Gomes-Neto M, Duraes AR, Conceicao LSR, Roever L, Liu T, Tse G, Biondi-Zoccai G, Goes ALB, Alves IGN, Ellingsen O, Carvalho VO (2019) Effect of aerobic exercise on peak oxygen consumption, VE/VCO2 slope, and health-related quality of life in patients with heart failure with preserved left ventricular ejection fraction: a systematic review and meta-analysis. Curr Atheroscler Rep 21(11):45. https://doi.org/10.1007/s11883-019-0806-6

    Article  PubMed  CAS  Google Scholar 

  11. Leggio M, Fusco A, Loreti C, Limongelli G, Bendini MG, Mazza A, Coraci D, Padua L (2019) Effects of exercise training in heart failure with preserved ejection fraction: an updated systematic literature review. Heart Fail Rev. https://doi.org/10.1007/s10741-019-09841-x

    Article  Google Scholar 

  12. Pandey A, Parashar A, Kumbhani D, Agarwal S, Garg J, Kitzman D, Levine B, Drazner M, Berry J (2015) Exercise training in patients with heart failure and preserved ejection fraction: meta-analysis of randomized control trials. Circulation Heart failure 8(1):33–40. https://doi.org/10.1161/circheartfailure.114.001615

    Article  PubMed  Google Scholar 

  13. Fukuta H, Goto T, Wakami K, Ohte N (2016) Effects of drug and exercise intervention on functional capacity and quality of life in heart failure with preserved ejection fraction: a meta-analysis of randomized controlled trials. Eur J Prev Cardiol 23(1):78–85. https://doi.org/10.1177/2047487314564729

    Article  PubMed  Google Scholar 

  14. Edelmann F, Gelbrich G, Düngen HD, Fröhling S, Wachter R, Stahrenberg R, Binder L, Töpper A, Lashki DJ, Schwarz S, Herrmann-Lingen C, Löffler M, Hasenfuss G, Halle M, Pieske B (2011) Exercise training improves exercise capacity and diastolic function in patients with heart failure with preserved ejection fraction: results of the Ex-DHF (Exercise training in Diastolic Heart Failure) pilot study. J Am Coll Cardiol 58(17):1780–1791. https://doi.org/10.1016/j.jacc.2011.06.054

    Article  PubMed  Google Scholar 

  15. Schmidt C, Moreira-Gonçalves D, Santos M, Leite-Moreira A, Oliveira J (2020) Physical activity and exercise training in heart failure with preserved ejection fraction: gathering evidence from clinical and pre-clinical studies. Heart Fail Rev . https://doi.org/10.1007/s10741-020-09973-5

    Article  Google Scholar 

  16. Crimi E, Ignarro LJ, Cacciatore F, Napoli C (2009) Mechanisms by which exercise training benefits patients with heart failure. Nature reviews Cardiology 6(4):292–300. https://doi.org/10.1038/nrcardio.2009.8

    Article  PubMed  Google Scholar 

  17. Cheng JM, Akkerhuis KM, Battes LC, van Vark LC, Hillege HL, Paulus WJ, Boersma E, Kardys I (2013) Biomarkers of heart failure with normal ejection fraction: a systematic review. Eur J Heart Fail 15(12):1350–1362. https://doi.org/10.1093/eurjhf/hft106

    Article  PubMed  CAS  Google Scholar 

  18. Sanders-van Wijk S, van Empel V, Davarzani N, Maeder MT, Handschin R, Pfisterer ME, Brunner-La Rocca HP (2015) Circulating biomarkers of distinct pathophysiological pathways in heart failure with preserved vs. reduced left ventricular ejection fraction. Eur J Heart Fail 17(10):1006–1014. https://doi.org/10.1002/ejhf.414

    Article  PubMed  CAS  Google Scholar 

  19. Kalogeropoulos A, Georgiopoulou V, Psaty BM, Rodondi N, Smith AL, Harrison DG, Liu Y, Hoffmann U, Bauer DC, Newman AB, Kritchevsky SB, Harris TB, Butler J (2010) Inflammatory markers and incident heart failure risk in older adults: the Health ABC (Health, Aging, and Body Composition) study. J Am Coll Cardiol 55(19):2129–2137. https://doi.org/10.1016/j.jacc.2009.12.045

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Franssen C, Chen S, Unger A, Korkmaz HI, De Keulenaer GW, Tschope C, Leite-Moreira AF, Musters R, Niessen HW, Linke WA, Paulus WJ, Hamdani N (2016) Myocardial microvascular inflammatory endothelial activation in heart failure with preserved ejection fraction. JACC Heart failure 4(4):312–324. https://doi.org/10.1016/j.jchf.2015.10.007

    Article  PubMed  Google Scholar 

  21. Westermann D, Lindner D, Kasner M, Zietsch C, Savvatis K, Escher F, von Schlippenbach J, Skurk C, Steendijk P, Riad A, Poller W, Schultheiss HP, Tschope C (2011) Cardiac inflammation contributes to changes in the extracellular matrix in patients with heart failure and normal ejection fraction. Circ Heart Fail 4(1):44–52. https://doi.org/10.1161/circheartfailure.109.931451

    Article  PubMed  Google Scholar 

  22. Juni RP, Kuster DWD, Goebel M, Helmes M, Musters RJP, van der Velden J, Koolwijk P, Paulus WJ, van Hinsbergh VWM (2019) Cardiac microvascular endothelial enhancement of cardiomyocyte function is impaired by inflammation and restored by empagliflozin. JACC Basic Transl Sci 4(5):575–591. https://doi.org/10.1016/j.jacbts.2019.04.003

    Article  PubMed  PubMed Central  Google Scholar 

  23. Zhang H, Park Y, Wu J, Chen XP, Lee S, Yang J, Dellsperger KC, Zhang C (2009) Role of TNF-α in vascular dysfunction. Clin Sci 116(3):219–230

    Article  CAS  Google Scholar 

  24. Van Buul JD, Fernandez-Borja M, Anthony EC, Hordijk PL (2005) Expression and localization of NOX2 and NOX4 in primary human endothelial cells. Antioxid Redox Signal 7(3–4):308–317. https://doi.org/10.1089/ars.2005.7.308

    Article  PubMed  Google Scholar 

  25. van Heerebeek L, Hamdani N, Falcao-Pires I, Leite-Moreira AF, Begieneman MP, Bronzwaer JG, van der Velden J, Stienen GJ, Laarman GJ, Somsen A, Verheugt FW, Niessen HW, Paulus WJ (2012) Low myocardial protein kinase G activity in heart failure with preserved ejection fraction. Circulation 126(7):830–839. https://doi.org/10.1161/circulationaha.111.076075

    Article  PubMed  Google Scholar 

  26. Borbely A, Falcao-Pires I, van Heerebeek L, Hamdani N, Edes I, Gavina C, Leite-Moreira AF, Bronzwaer JG, Papp Z, van der Velden J, Stienen GJ, Paulus WJ (2009) Hypophosphorylation of the Stiff N2B titin isoform raises cardiomyocyte resting tension in failing human myocardium. Circ Res 104(6):780–786. https://doi.org/10.1161/circresaha.108.193326

    Article  PubMed  CAS  Google Scholar 

  27. Takimoto E, Champion HC, Li M, Belardi D, Ren S, Rodriguez ER, Bedja D, Gabrielson KL, Wang Y, Kass DA (2005) Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med 11(2):214–222. https://doi.org/10.1038/nm1175

    Article  PubMed  CAS  Google Scholar 

  28. Hofmann F (2018) A concise discussion of the regulatory role of cGMP kinase I in cardiac physiology and pathology. Basic Res Cardiol 113(4):31. https://doi.org/10.1007/s00395-018-0690-1

    Article  PubMed  CAS  Google Scholar 

  29. Mohammed SF, Hussain S, Mirzoyev SA, Edwards WD, Maleszewski JJ, Redfield MM (2015) Coronary microvascular rarefaction and myocardial fibrosis in heart failure with preserved ejection fraction. Circulation 131(6):550–559. https://doi.org/10.1161/circulationaha.114.009625

    Article  PubMed  Google Scholar 

  30. Xu Z, Gu HP, Gu Y, Sun W, Yu K, Zhang XW, Kong XQ (2018) Increased index of microcirculatory resistance in older patients with heart failure with preserved ejection fraction. J Geriatr Cardiol 15(11):687–694. https://doi.org/10.11909/j.issn.1671-5411.2018.11.010

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Zeng H, Chen JX (2019) Microvascular Rarefaction and Heart Failure With Preserved Ejection Fraction. Front Cardiovasc Med 6:15. https://doi.org/10.3389/fcvm.2019.00015

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  32. Rauchhaus M, Doehner W, Francis DP, Davos C, Kemp M, Liebenthal C, Niebauer J, Hooper J, Volk HD, Coats AJ, Anker SD (2000) Plasma cytokine parameters and mortality in patients with chronic heart failure. Circulation 102(25):3060–3067

    Article  CAS  PubMed  Google Scholar 

  33. Tsutamoto T, Hisanaga T, Wada A, Maeda K, Ohnishi M, Fukai D, Mabuchi N, Sawaki M, Kinoshita M (1998) Interleukin-6 spillover in the peripheral circulation increases with the severity of heart failure, and the high plasma level of interleukin-6 is an important prognostic predictor in patients with congestive heart failure. J Am Coll Cardiol 31(2):391–398

    Article  CAS  PubMed  Google Scholar 

  34. Pearson MJ, Mungovan SF, Smart NA (2018) Effect of aerobic and resistance training on inflammatory markers in heart failure patients: systematic review and meta-analysis. Heart Fail Rev 23(2):209–223. https://doi.org/10.1007/s10741-018-9677-0

    Article  PubMed  CAS  Google Scholar 

  35. Kitzman DW, Brubaker P, Morgan T, Haykowsky M, Hundley G, Kraus WE, Eggebeen J, Nicklas BJ (2016) Effect of caloric restriction or aerobic exercise training on peak oxygen consumption and quality of life in obese older patients with heart failure with preserved ejection fraction: a randomized clinical trial. JAMA 315(1):36–46. https://doi.org/10.1001/jama.2015.17346

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Trippel TD, Holzendorf V, Halle M, Gelbrich G, Nolte K, Duvinage A, Schwarz S, Rutscher T, Wiora J, Wachter R, Herrmann-Lingen C, Duengen HD, Hasenfuss G, Pieske B, Edelmann F (2017) Ghrelin and hormonal markers under exercise training in patients with heart failure with preserved ejection fraction: results from the Ex-DHF pilot study. ESC heart failure 4(1):56–65. https://doi.org/10.1002/ehf2.12109

    Article  PubMed  Google Scholar 

  37. Aksoy S, Findikoglu G, Ardic F, Rota S, Dursunoglu D (2015) Effect of 10-week supervised moderate-intensity intermittent vs. continuous aerobic exercise programs on vascular adhesion molecules in patients with heart failure. Am J Phys Med Rehabil 94(10 Suppl 1):898–911. https://doi.org/10.1097/phm.0000000000000306

    Article  PubMed  Google Scholar 

  38. Adamopoulos S, Parissis J, Karatzas D, Kroupis C, Georgiadis M, Karavolias G, Paraskevaidis J, Koniavitou K, Coats AJ, Kremastinos DT (2002) Physical training modulates proinflammatory cytokines and the soluble Fas/soluble Fas ligand system in patients with chronic heart failure. J Am Coll Cardiol 39(4):653–663

    Article  CAS  PubMed  Google Scholar 

  39. Alves JP, Nunes RB, Stefani GP, Dal Lago P (2014) Resistance training improves hemodynamic function, collagen deposition and inflammatory profiles: experimental model of heart failure. PLoS ONE 9(10). https://doi.org/10.1371/journal.pone.0110317

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Nunes RB, Alves JP, Kessler LP, Dal Lago P (2013) Aerobic exercise improves the inflammatory profile correlated with cardiac remodeling and function in chronic heart failure rats. Clinics (Sao Paulo, Brazil) 68(6):876–882. https://doi.org/10.6061/clinics/2013(06)24

    Article  Google Scholar 

  41. Khan MS, Samman Tahhan A, Vaduganathan M, Greene SJ, Alrohaibani A, Anker SD, Vardeny O, Fonarow GC, Butler J (2020) Trends in prevalence of comorbidities in heart failure clinical trials. Eur J Heart Fail 22(6):1032–1042. https://doi.org/10.1002/ejhf.1818

    Article  PubMed  Google Scholar 

  42. Edwards KM, Ziegler MG, Mills PJ (2007) The potential anti-inflammatory benefits of improving physical fitness in hypertension. J Hypertens 25(8):1533–1542. https://doi.org/10.1097/HJH.0b013e328165ca67

    Article  PubMed  CAS  Google Scholar 

  43. Barrows IR, Ramezani A, Raj DS (2019) Inflammation, immunity, and oxidative stress in hypertension-partners in crime? Adv Chronic Kidney Dis 26(2):122–130. https://doi.org/10.1053/j.ackd.2019.03.001

    Article  PubMed  PubMed Central  Google Scholar 

  44. Hjelstuen A, Anderssen SA, Holme I, Seljeflot I, Klemsdal TO (2006) Markers of inflammation are inversely related to physical activity and fitness in sedentary men with treated hypertension. Am J Hypertens 19(7):669–675; discussion 676-667. https://doi.org/10.1016/j.amjhyper.2005.11.012

    Article  PubMed  Google Scholar 

  45. Uurtuya S, Kotani K, Koibuchi H, Miyamoto M, Kario K, Yamada T, Taniguchi N (2010) The relationship between serum C-reactive protein and daily physical activity in Japanese hypertensive patients. Clin Exp Hypertens 32(8):517–522. https://doi.org/10.3109/10641963.2010.496512

    Article  PubMed  CAS  Google Scholar 

  46. Lima LG, Bonardi JM, Campos GO, Bertani RF, Scher LM, Louzada-Junior P, Moriguti JC, Ferriolli E, Lima NK (2015) Effect of aerobic training and aerobic and resistance training on the inflammatory status of hypertensive older adults. Aging Clin Exp Res 27(4):483–489. https://doi.org/10.1007/s40520-014-0307-y

    Article  PubMed  Google Scholar 

  47. Boeno FP, Ramis TR, Munhoz SV, Farinha JB, Moritz CEJ, Leal-Menezes R, Ribeiro JL, Christou DD, Reischak-Oliveira A (2020) Effect of aerobic and resistance exercise training on inflammation, endothelial function and ambulatory blood pressure in middle-aged hypertensive patients. J Hypertens 38(12):2501–2509. https://doi.org/10.1097/hjh.0000000000002581

    Article  PubMed  CAS  Google Scholar 

  48. Ahn N, Kim K (2020) Can active aerobic exercise reduce the risk of cardiovascular disease in prehypertensive elderly women by improving HDL cholesterol and inflammatory markers? Int J Environ Res Public Health 17(16). https://doi.org/10.3390/ijerph17165910

  49. Lamina S, Okoye GC (2012) Effect of interval exercise training programme on C-reactive protein in the non-pharmacological management of hypertension: a randomized controlled trial. Afr J Med Med Sci 41(4):379–386

    PubMed  CAS  Google Scholar 

  50. Okita K, Nishijima H, Murakami T, Nagai T, Morita N, Yonezawa K, Iizuka K, Kawaguchi H, Kitabatake A (2004) Can exercise training with weight loss lower serum C-reactive protein levels? Arterioscler Thromb Vasc Biol 24(10):1868–1873. https://doi.org/10.1161/01.Atv.0000140199.14930.32

    Article  PubMed  CAS  Google Scholar 

  51. Pedersen BK (2017) Anti-inflammatory effects of exercise: role in diabetes and cardiovascular disease. Eur J Clin Investig 47(8):600–611. https://doi.org/10.1111/eci.12781

    Article  CAS  Google Scholar 

  52. Roberts CK, Won D, Pruthi S, Lin SS, Barnard RJ (2006) Effect of a diet and exercise intervention on oxidative stress, inflammation and monocyte adhesion in diabetic men. Diabetes Res Clin Pract 73(3):249–259. https://doi.org/10.1016/j.diabres.2006.02.013

    Article  PubMed  CAS  Google Scholar 

  53. Zoppini G, Targher G, Zamboni C, Venturi C, Cacciatori V, Moghetti P, Muggeo M (2006) Effects of moderate-intensity exercise training on plasma biomarkers of inflammation and endothelial dysfunction in older patients with type 2 diabetes. Nutr Metab Cardiovasc Dis 16(8):543–549. https://doi.org/10.1016/j.numecd.2005.09.004

    Article  PubMed  CAS  Google Scholar 

  54. Hayashino Y, Jackson JL, Hirata T, Fukumori N, Nakamura F, Fukuhara S, Tsujii S, Ishii H (2014) Effects of exercise on C-reactive protein, inflammatory cytokine and adipokine in patients with type 2 diabetes: a meta-analysis of randomized controlled trials. Metabol: Clin Exp 63(3):431–440. https://doi.org/10.1016/j.metabol.2013.08.018

    Article  CAS  Google Scholar 

  55. Teixeira de Lemos E, Pinto R, Oliveira J, Garrido P, Sereno J, Mascarenhas-Melo F, Pascoa-Pinheiro J, Teixeira F, Reis F (2011) Differential effects of acute (extenuating) and chronic (training) exercise on inflammation and oxidative stress status in an animal model of type 2 diabetes mellitus. Mediators Inflamm 2011. https://doi.org/10.1155/2011/253061

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Visser M, Bouter LM, McQuillan GM, Wener MH, Harris TB (1999) Elevated C-reactive protein levels in overweight and obese adults. JAMA 282(22):2131–2135. https://doi.org/10.1001/jama.282.22.2131

    Article  PubMed  CAS  Google Scholar 

  57. Roytblat L, Rachinsky M, Fisher A, Greemberg L, Shapira Y, Douvdevani A, Gelman S (2000) Raised interleukin-6 levels in obese patients. Obes Res 8(9):673–675. https://doi.org/10.1038/oby.2000.86

    Article  PubMed  CAS  Google Scholar 

  58. Kern PA, Saghizadeh M, Ong JM, Bosch RJ, Deem R, Simsolo RB (1995) The expression of tumor necrosis factor in human adipose tissue. Regulation by obesity, weight loss, and relationship to lipoprotein lipase. J Clin Investig 95(5):2111–2119. https://doi.org/10.1172/jci117899

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Olson TP, Dengel DR, Leon AS, Schmitz KH (2007) Changes in inflammatory biomarkers following one-year of moderate resistance training in overweight women. Int J Obes 31(6):996–1003. https://doi.org/10.1038/sj.ijo.0803534

    Article  CAS  Google Scholar 

  60. Campbell PT, Campbell KL, Wener MH, Wood BL, Potter JD, McTiernan A, Ulrich CM (2009) A yearlong exercise intervention decreases CRP among obese postmenopausal women. Med Sci Sports Exerc 41(8):1533–1539. https://doi.org/10.1249/MSS.0b013e31819c7feb

    Article  PubMed  Google Scholar 

  61. Alizaei Yousefabadi H, Niyazi A, Alaee S, Fathi M, Mohammad Rahimi GR (2020) Anti-inflammatory effects of exercise on metabolic syndrome patients: a systematic review and meta-analysis. Biol Res Nurs. https://doi.org/10.1177/1099800420958068

  62. Gevaert AB, Lemmens K, Vrints CJ, Van Craenenbroeck EM (2017) Targeting endothelial function to treat heart failure with preserved ejection fraction: the promise of exercise training. Oxid Med Cell Longev. https://doi.org/10.1155/2017/4865756

  63. Akiyama E, Sugiyama S, Matsuzawa Y, Konishi M, Suzuki H, Nozaki T, Ohba K, Matsubara J, Maeda H, Horibata Y, Sakamoto K, Sugamura K, Yamamuro M, Sumida H, Kaikita K, Iwashita S, Matsui K, Kimura K, Umemura S, Ogawa H (2012) Incremental prognostic significance of peripheral endothelial dysfunction in patients with heart failure with normal left ventricular ejection fraction. J Am Coll Cardiol 60(18):1778–1786. https://doi.org/10.1016/j.jacc.2012.07.036

    Article  PubMed  Google Scholar 

  64. Gielen S, Adams V, Mobius-Winkler S, Linke A, Erbs S, Yu J, Kempf W, Schubert A, Schuler G, Hambrecht R (2003) Anti-inflammatory effects of exercise training in the skeletal muscle of patients with chronic heart failure. J Am Coll Cardiol 42(5):861–868. https://doi.org/10.1016/s0735-1097(03)00848-9

    Article  PubMed  CAS  Google Scholar 

  65. Kitzman DW, Brubaker PH, Herrington DM, Morgan TM, Stewart KP, Hundley WG, Abdelhamed A, Haykowsky MJ (2013) Effect of endurance exercise training on endothelial function and arterial stiffness in older patients with heart failure and preserved ejection fraction: a randomized, controlled, single-blind trial. J Am Coll Cardiol 62(7):584–592. https://doi.org/10.1016/j.jacc.2013.04.033

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Pearson MJ, Smart NA (2017) Effect of exercise training on endothelial function in heart failure patients: a systematic review meta-analysis. Int J Cardiol 231:234–243. https://doi.org/10.1016/j.ijcard.2016.12.145

    Article  PubMed  CAS  Google Scholar 

  67. Qiu S, Cai X, Yin H, Sun Z, Zügel M, Steinacker JM, Schumann U (2018) Exercise training and endothelial function in patients with type 2 diabetes: a meta-analysis. Cardiovasc Diabetol 17(1):64. https://doi.org/10.1186/s12933-018-0711-2

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Adams V, Alves M, Fischer T, Rolim N, Werner S, Schutt N, Bowen TS, Linke A, Schuler G, Wisloff U (2015) High-intensity interval training attenuates endothelial dysfunction in a Dahl salt-sensitive rat model of heart failure with preserved ejection fraction. J Appl Physiol 119(6):745–752. https://doi.org/10.1152/japplphysiol.01123.2014

    Article  PubMed  CAS  Google Scholar 

  69. Schmederer Z, Rolim N, Bowen TS, Linke A, Wisloff U, Adams V (2018) Endothelial function is disturbed in a hypertensive diabetic animal model of HFpEF: Moderate continuous vs. high intensity interval training. Int J Cardiol 273:147–154. https://doi.org/10.1016/j.ijcard.2018.08.087

    Article  PubMed  Google Scholar 

  70. Pacher P, Beckman JS, Liaudet L (2007) Nitric oxide and peroxynitrite in health and disease. Physiol Rev 87(1):315–424. https://doi.org/10.1152/physrev.00029.2006

    Article  CAS  PubMed  Google Scholar 

  71. Adams V, Reich B, Uhlemann M, Niebauer J (2017) Molecular effects of exercise training in patients with cardiovascular disease: focus on skeletal muscle, endothelium, and myocardium. Am J Physiol Heart Circ Physiol 313(1):H72-H88. https://doi.org/10.1152/ajpheart.00470.2016

    Article  PubMed  Google Scholar 

  72. Baldassarri F, Schwedhelm E, Atzler D, Böger RH, Cordts K, Haller B, Pressler A, Müller S, Suchy C, Wachter R, Düngen HD, Hasenfuss G, Pieske B, Halle M, Edelmann F, Duvinage A (2018) Relationship between exercise intervention and NO pathway in patients with heart failure with preserved ejection fraction. Biomarkers 23(6):540–550. https://doi.org/10.1080/1354750x.2018.1460762

    Article  PubMed  CAS  Google Scholar 

  73. Gomes VA, Casella-Filho A, Chagas AC, Tanus-Santos JE (2008) Enhanced concentrations of relevant markers of nitric oxide formation after exercise training in patients with metabolic syndrome. Nitric Oxide 19(4):345–350. https://doi.org/10.1016/j.niox.2008.08.005

    Article  PubMed  CAS  Google Scholar 

  74. Niebauer J, Clark AL, Webb-Peploe KM, Böger R, Coats AJ (2005) Home-based exercise training modulates pro-oxidant substrates in patients with chronic heart failure. Eur J Heart Fail 7(2):183–188. https://doi.org/10.1016/j.ejheart.2004.06.001

    Article  PubMed  CAS  Google Scholar 

  75. Linke A, Adams V, Schulze PC, Erbs S, Gielen S, Fiehn E, Möbius-Winkler S, Schubert A, Schuler G, Hambrecht R (2005) Antioxidative effects of exercise training in patients with chronic heart failure: increase in radical scavenger enzyme activity in skeletal muscle. Circulation 111(14):1763–1770. https://doi.org/10.1161/01.Cir.0000165503.08661.E5

    Article  PubMed  CAS  Google Scholar 

  76. Jarrete AP, Novais IP, Nunes HA, Puga GM, Delbin MA, Zanesco A (2014) Influence of aerobic exercise training on cardiovascular and endocrine-inflammatory biomarkers in hypertensive postmenopausal women. J Clin Transl Endocrinol 1(3):108–114. https://doi.org/10.1016/j.jcte.2014.07.004

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Agarwal D, Haque M, Sriramula S, Mariappan N, Pariaut R, Francis J (2009) Role of proinflammatory cytokines and redox homeostasis in exercise-induced delayed progression of hypertension in spontaneously hypertensive rats. Hypertension 54(6):1393–1400. https://doi.org/10.1161/hypertensionaha.109.135459

    Article  PubMed  CAS  Google Scholar 

  78. Lin YY, Hong Y, Zhou MC, Huang HL, Shyu WC, Chen JS, Ting H, Cheng YJ, Yang AL, Lee SD (2020) Exercise training attenuates cardiac inflammation and fibrosis in hypertensive ovariectomized rats. J Appl Physiol (1985) 128(4):1033–1043. https://doi.org/10.1152/japplphysiol.00844.2019

    Article  Google Scholar 

  79. Scott SN, Shepherd SO, Hopkins N, Dawson EA, Strauss JA, Wright DJ, Cooper RG, Kumar P, Wagenmakers AJM, Cocks M (2019) Home-hit improves muscle capillarisation and eNOS/NAD(P)Hoxidase protein ratio in obese individuals with elevated cardiovascular disease risk. J Physiol 597(16):4203–4225. https://doi.org/10.1113/jp278062

    Article  PubMed  CAS  Google Scholar 

  80. Cocks M, Shaw CS, Shepherd SO, Fisher JP, Ranasinghe A, Barker TA, Wagenmakers AJ (2016) Sprint interval and moderate-intensity continuous training have equal benefits on aerobic capacity, insulin sensitivity, muscle capillarisation and endothelial eNOS/NAD(P)Hoxidase protein ratio in obese men. J Physiol 594(8):2307–2321. https://doi.org/10.1113/jphysiol.2014.285254

    Article  PubMed  CAS  Google Scholar 

  81. Effting PS, Brescianini SMS, Sorato HR, Fernandes BB, Fidelis G, Silva P, Silveira PCL, Nesi RT, Ceddia RB, Pinho RA (2019) Resistance Exercise Modulates Oxidative Stress Parameters and TNF-alpha Content in the Heart of Mice with Diet-Induced Obesity. Arq Bras Cardiol 112(5):545–552. https://doi.org/10.5935/abc.20190072

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Sixt S, Beer S, Blüher M, Korff N, Peschel T, Sonnabend M, Teupser D, Thiery J, Adams V, Schuler G, Niebauer J (2010) Long- but not short-term multifactorial intervention with focus on exercise training improves coronary endothelial dysfunction in diabetes mellitus type 2 and coronary artery disease. Eur Heart J 31(1):112–119. https://doi.org/10.1093/eurheartj/ehp398

    Article  PubMed  CAS  Google Scholar 

  83. Frisbee JC (2005) Reduced nitric oxide bioavailability contributes to skeletal muscle microvessel rarefaction in the metabolic syndrome. Am J Physiol Regul Integr Comp Physiol 289(2):R307-R316. https://doi.org/10.1152/ajpregu.00114.2005

    Article  PubMed  CAS  Google Scholar 

  84. Sandri M, Viehmann M, Adams V, Rabald K, Mangner N, Höllriegel R, Lurz P, Erbs S, Linke A, Kirsch K, Möbius-Winkler S, Thiery J, Teupser D, Hambrecht R, Schuler G, Gielen S (2016) Chronic heart failure and aging - effects of exercise training on endothelial function and mechanisms of endothelial regeneration: results from the Leipzig Exercise Intervention in Chronic heart failure and Aging (LEICA) study. Eur J Prev Cardiol 23(4):349–358. https://doi.org/10.1177/2047487315588391

    Article  PubMed  Google Scholar 

  85. Cavalcante SL, Lopes S, Bohn L, Cavero-Redondo I, Álvarez-Bueno C, Viamonte S, Santos M, Oliveira J, Ribeiro F (2019) Effects of exercise on endothelial progenitor cells in patients with cardiovascular disease: a systematic review and meta-analysis of randomized controlled trials. Rev Port Cardiol 38(11):817–827. https://doi.org/10.1016/j.repc.2019.02.016

    Article  PubMed  Google Scholar 

  86. Mortensen SP, Winding KM, Iepsen UW, Munch GW, Marcussen N, Hellsten Y, Pedersen BK, Baum O (2019) The effect of two exercise modalities on skeletal muscle capillary ultrastructure in individuals with type 2 diabetes. Scand J Med Sci Sports 29(3):360–368. https://doi.org/10.1111/sms.13348

    Article  PubMed  Google Scholar 

  87. Machado MV, Martins RL, Borges J, Antunes BR, Estato V, Vieira AB, Tibiriçá E (2016) Exercise training reverses structural microvascular rarefaction and improves endothelium-dependent microvascular reactivity in rats with diabetes. Metab Syndr Relat Disord 14(6):298–304. https://doi.org/10.1089/met.2015.0146

    Article  PubMed  CAS  Google Scholar 

  88. Frisbee JC, Samora JB, Peterson J, Bryner R (2006) Exercise training blunts microvascular rarefaction in the metabolic syndrome. Am J Physiol Heart Circ Physiol 291(5):H2483-2492. https://doi.org/10.1152/ajpheart.00566.2006

    Article  PubMed  CAS  Google Scholar 

  89. Zile MR, Baicu CF, Ikonomidis JS, Stroud RE, Nietert PJ, Bradshaw AD, Slater R, Palmer BM, Van Buren P, Meyer M, Redfield MM, Bull DA, Granzier HL, LeWinter MM (2015) Myocardial stiffness in patients with heart failure and a preserved ejection fraction: contributions of collagen and titin. Circulation 131(14):1247–1259. https://doi.org/10.1161/circulationaha.114.013215

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Marshall KD, Muller BN, Krenz M, Hanft LM, McDonald KS, Dellsperger KC, Emter CA (2013) Heart failure with preserved ejection fraction: chronic low-intensity interval exercise training preserves myocardial O2 balance and diastolic function. J Appl Physiol 114(1):131–147. https://doi.org/10.1152/japplphysiol.01059.2012

    Article  PubMed  Google Scholar 

  91. Alves JP, Nunes RB, Ferreira DDC, Stefani GP, Jaenisch RB, Lago PD (2017) High-intensity resistance training alone or combined with aerobic training improves strength, heart function and collagen in rats with heart failure. Am J Transl Res 9(12):5432–5441

    PubMed  PubMed Central  CAS  Google Scholar 

  92. Slater RE, Strom JG, Granzier H (2017) Effect of exercise on passive myocardial stiffness in mice with diastolic dysfunction. J Mol Cell Cardiol 108:24–33. https://doi.org/10.1016/j.yjmcc.2017.04.006

    Article  PubMed  CAS  Google Scholar 

  93. Lee Y, Kwak HB, Hord J, Kim JH, Lawler JM (2015) Exercise training attenuates age-dependent elevation of angiotensin II type 1 receptor and Nox2 signaling in the rat heart. Exp Gerontol 70:163–173. https://doi.org/10.1016/j.exger.2015.07.016

    Article  PubMed  CAS  Google Scholar 

  94. Guzzoni V, Marqueti RC, Durigan JLQ, Faustino de Carvalho H, Lino RLB, Mekaro MS, Costa Santos TO, Mecawi AS, Rodrigues JA, Hord JM, Lawler JM, Davel AP, Selistre-de-Araújo HS (2017) Reduced collagen accumulation and augmented MMP-2 activity in left ventricle of old rats submitted to high-intensity resistance training. J Appl Physiol 123(3):655–663. https://doi.org/10.1152/japplphysiol.01090.2016

    Article  PubMed  CAS  Google Scholar 

  95. Dunlay SM, Roger VL, Redfield MM (2017) Epidemiology of heart failure with preserved ejection fraction. Nat Rev Cardiol 14(10):591–602. https://doi.org/10.1038/nrcardio.2017.65

    Article  PubMed  Google Scholar 

  96. Loffredo FS, Nikolova AP, Pancoast JR, Lee RT (2014) Heart failure with preserved ejection fraction: molecular pathways of the aging myocardium. Circ Res 115(1):97–107. https://doi.org/10.1161/circresaha.115.302929

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Wang SQ, Li D, Yuan Y (2019) Long-term moderate intensity exercise alleviates myocardial fibrosis in type 2 diabetic rats via inhibitions of oxidative stress and TGF-β1/Smad pathway. J Physiol Sci 69(6):861–873. https://doi.org/10.1007/s12576-019-00696-3

    Article  PubMed  CAS  Google Scholar 

  98. Hidalgo C, Saripalli C, Granzier HL (2014) Effect of exercise training on post-translational and post-transcriptional regulation of titin stiffness in striated muscle of wild type and IG KO mice. Arch Biochem Biophys 552–553:100–107. https://doi.org/10.1016/j.abb.2014.02.010

    Article  PubMed  CAS  Google Scholar 

  99. van Heerebeek L, Borbély A, Niessen HW, Bronzwaer JG, van der Velden J, Stienen GJ, Linke WA, Laarman GJ, Paulus WJ (2006) Myocardial structure and function differ in systolic and diastolic heart failure. Circulation 113(16):1966–1973. https://doi.org/10.1161/circulationaha.105.587519

    Article  PubMed  Google Scholar 

  100. Nakamura M, Sadoshima J (2018) Mechanisms of physiological and pathological cardiac hypertrophy. Nat Rev Cardiol 15(7):387–407. https://doi.org/10.1038/s41569-018-0007-y

    Article  PubMed  CAS  Google Scholar 

  101. Johnson EJ, Dieter BP, Marsh SA (2015) Evidence for distinct effects of exercise in different cardiac hypertrophic disorders. Life Sci 123:100–106. https://doi.org/10.1016/j.lfs.2015.01.007

    Article  PubMed  CAS  Google Scholar 

  102. Fukuta H, Goto T, Wakami K, Kamiya T, Ohte N (2019) Effects of exercise training on cardiac function, exercise capacity, and quality of life in heart failure with preserved ejection fraction: a meta-analysis of randomized controlled trials. Heart Fail Rev 24(4):535–547. https://doi.org/10.1007/s10741-019-09774-5

    Article  PubMed  Google Scholar 

  103. Emter CA, Baines CP (2010) Low-intensity aerobic interval training attenuates pathological left ventricular remodeling and mitochondrial dysfunction in aortic-banded miniature swine. American journal of physiology Heart and circulatory physiology 299(5):H1348-1356. https://doi.org/10.1152/ajpheart.00578.2010

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Vega RB, Konhilas JP, Kelly DP, Leinwand LA (2017) Molecular mechanisms underlying cardiac adaptation to exercise. Cell Metab 25(5):1012–1026. https://doi.org/10.1016/j.cmet.2017.04.025

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Funding

Cardiovascular R&D Center and the Centre of Physical Activity, Health and Leisure (CIAFEL) are supported by national funds through FCT Fundação para a Ciência e Tecnologia, I.P. (UIDB/00617/2020is and UID/IC/00051/2019, respectively).

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  1. Cardiovascular R&D Center (UnIC) and Department of Physiology and Cardiothoracic Surgery, Faculty of Medicine, University of Porto, Porto, Portugal

    Eliane Jaconiano

  2. Centre of Physical Activity, Health and Leisure (CIAFEL), Faculty of Sport, University of Porto, Porto, Portugal

    Daniel Moreira-Gonçalves

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  1. Eliane Jaconiano
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All authors contributed to the study conception and design. Literature search, data analysis, and the first draft of the manuscript were performed by Eliane Jaconiano. Daniel Moreira-Gonçalves commented on previous versions of the manuscript and critically revised the final work. All authors read and approved the final manuscript.

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Jaconiano, E., Moreira-Gonçalves, D. Unveiling the role of exercise training in targeting the inflammatory paradigm of heart failure with preserved ejection fraction: a narrative review. Heart Fail Rev 27, 163–190 (2022). https://doi.org/10.1007/s10741-021-10138-1

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