Defining the Specific Skeletal Muscle Adaptations Responsible for Exercise Training Improvements in Heart Failure With Preserved Ejection Fraction

HomeCirculation: Heart FailureVol. 15, No. 10Defining the Specific Skeletal Muscle Adaptations Responsible for Exercise Training Improvements in Heart Failure With Preserved Ejection Fraction Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBDefining the Specific Skeletal Muscle Adaptations Responsible for Exercise Training Improvements in Heart Failure With Preserved Ejection Fraction Wesley J. Tucker and Dalane W. Kitzman Wesley J. TuckerWesley J. Tucker Department of Nutrition and Food Sciences, Texas Woman's University, Houston (W.J.T.). and Dalane W. KitzmanDalane W. Kitzman Correspondence to: Dalane W. Kitzman, MD, Sections on Cardiovascular Medicine and Geriatrics/Gerontology, Kermit Glenn Phillips II Chair in Cardiovascular Medicine, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1045. Email E-mail Address: [email protected] Cardiovascular Medicine and Geriatrics Sections, Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC (D.W.K.). Originally published6 Oct 2022https://doi.org/10.1161/CIRCHEARTFAILURE.122.010003Circulation: Heart Failure. 2022;15This article is a commentary on the followingImpact of Different Training Modalities on Molecular Alterations in Skeletal Muscle of Patients With Heart Failure With Preserved Ejection Fraction: A Substudy of the OptimEx TrialOther version(s) of this articleYou are viewing the most recent version of this article. Previous versions: October 6, 2022: Ahead of Print Heart failure with preserved ejection fraction (HFpEF), the dominant form of HF in the United States, is associated with significant morbidity and mortality.1 The primary chronic symptom in chronic, stable HFpEF patients is severe exercise intolerance, measured objectively as reduced oxygen uptake during peak aerobic exercise (VO2peak) and is a major independent predictor of quality of life, hospitalization, and mortality.2–4 As such, a major goal of therapy is to improve exercise tolerance in patients with HFpEF.See Article by Winzer et alExercise training (ET) is a proven effective therapy for improving VO2peak in HFpEF.5 Specifically, a 2016 meta-analysis by Fukuta et al5 reported that ET resulted in a large improvement of 2.3 mL/kg per minute for VO2peak compared with usual care in patients with HFpEF. In contrast, most pharmacotherapies do not improve VO2peak in patients with HFpEF.5 Accordingly, understanding the mechanisms responsible for reduced VO2peak and its improvement with ET is critical to developing novel therapeutic approaches to improve exercise tolerance in HFpEF.The reduced VO2peak in HFpEF is secondary to central (cardiac) and peripheral abnormalities that reduce oxygen delivery and/or utilization by skeletal muscle during exercise.2,6 A number of invasive hemodynamic studies have demonstrated that patients with HFpEF have reduced peak exercise cardiac output secondary to lower heart rate and stroke volume responses.6 However, noncardiac peripheral factors are also a major contributor to lower VO2peak.2,6 In fact, Haykowsky et al2 reported that the strongest independent predictor of VO2peak was the change in arteriovenous oxygen difference (a-vO2diff) from rest to peak exercise in older patients with HFpEF. This impaired ability to augment a-vO2diff during exercise may be related to intrinsic skeletal muscle abnormalities that underlie skeletal muscle oxygen delivery and/or utilization. Indeed, patients with HFpEF present with multiple skeletal muscle abnormalities including skeletal muscle atrophy, decreased oxidative capacity, and mitochondrial volume, which are all associated with severely reduced exercise tolerance.7–9 Furthermore, ET seems to have little effect on peak exercise cardiac output, while peak exercise a-vO2diff increases significantly and accounts for >90% of the improvement in VO2peak.10,11 These findings suggest that increases in VO2peak following ET in HFpEF may be mediated primarily by improvements in skeletal muscle morphology or oxidative capacity. However, no study to date has examined changes in skeletal muscle morphology and oxidative capacity following ET in patients with HFpEF.In this issue of Circulation: Heart Failure, Winzer et al12 aimed to fill this important knowledge gap by assessing detailed molecular changes in skeletal muscle following ET in patients with HFpEF. The current study is a substudy of the Optimex trial,13 a large multicenter clinical trial which evaluated the efficacy of 2 different ET modalities (moderate continuous training [MCT] and high-intensity interval training [HIIT]) versus guideline-based physical activity counseling (control group) over 12 months in 180 outpatients with HFpEF. The interventions included 3 months of supervised ET, followed by 9 months of home-based ET. The primary findings of the Optimex trial were that both ET modalities resulted in a statistically significant increase in VO2peak (MCT: +1.6 mL/kg/min, HIIT: +1.1 mL/kg/min) versus controls (−0.6 mL/kg/min) at 3 months. However, there were no differences between ET modalities, and the improvements in VO2peak observed at 3 months were no longer present at 12 months.In this sub-study of the Optimex trial, Winzer et al12 collected muscle biopsies from the vastus lateralis muscle of 41 HFpEF patients (15 in MCT, 14 in HIIT, 12 in control) at baseline and 3 months after supervised ET. In addition, muscle biopsies were also taken in 24 HFpEF patients (8 in MCT, 7 in HIIT, 9 in control) at 12 months. Skeletal muscle tissue was analyzed to assess changes in molecular markers of skeletal muscle oxidative capacity (oxidative enzyme activity and fiber type distribution) and muscle atrophy. Change in skeletal muscle satellite cell content was also measured. To assess the overall effects of ET on skeletal muscle molecular markers, data from the MCT and HIIT groups were pooled and compared with control, in addition to analyzing differences between each group.The major new finding by Winzer et al12 is that 3 months of ET significantly increases mitochondrial enzyme activity (citrate synthase and mitochondrial complex-I) and expression (mitochondrial complex I, II, and IV) in skeletal muscle. These effects appeared greater with HIIT than MCT. These beneficial effects were no longer detectable at 12 months. Furthermore, 3 months of HIIT significantly reduced molecular markers of muscle atrophy (MuRF1 and Trim72 expression), with no significant changes observed with MCT. However, these initial favorable reductions in molecular markers of muscle atrophy associated with HIIT were also no longer observed at 12 months. Finally, the investigators also observed a significant increase in skeletal muscle satellite cells (Pax7 mRNA expression) after 3 months of HIIT, with no changes observed with MCT. Furthermore, subsequent analyses after 3 months of HIIT revealed greater increases in both the proliferative and differentiation capacities of the satellite cells.The study by Winzer et al12 provides several important additions to the scientific literature. This is the first study in humans to report detailed molecular markers of skeletal muscle oxidative capacity following ET in patients with HFpEF. In addition, this is the first study to investigate whether different modes of ET (MCT or HIIT) elicit different skeletal muscle adaptations in HFpEF. In the current study, improvements in skeletal muscle oxidative enzyme capacity (increases in mitochondrial enzyme activity and expression) appeared larger after 3 months of HIIT than MCT, although both MCT and HIIT improved VO2peak by a similar extent. The reasons for this disparity by training modality are uncertain. It may be that other factors contribute more strongly to training-related increases in VO2peak following MCT in HFpEF. Several studies10,11,14 have assessed changes in resting and peak exercise cardiac function following MCT in patients with HFpEF and found little to no change, suggesting that central (cardiac) adaptations play at most a minor role in the improved VO2peak with MCT. Instead, improvements in VO2peak with MCT may be driven by improvements in peripheral vascular and/or skeletal muscle adaptations. Kitzman et al14 previously showed that 16 weeks of MCT did not change large conduit artery stiffness or endothelial function in patients with HFpEF. However, no study to date has evaluated the effect of MCT on microvascular function and convective/diffusive oxygen transport within skeletal muscle in HFpEF. Given that prior work indicates that microvascular dysfunction is present in patients with HFpEF,15 future studies should examine whether MCT improves microvascular function and oxygen delivery within skeletal muscle, and whether these adaptations contribute to overall improvements in VO2peak.Winzer et al12 are also the first to study the effects of ET on molecular markers of skeletal muscle atrophy in patients with HFpEF. After 3 months of HIIT, molecular markers of skeletal muscle atrophy (MuRF1 and Trim72 expression) were significantly reduced. Furthermore, HIIT significantly increased skeletal muscle satellite cells and showed greater increases in both the proliferative and differentiation capacities of satellite cells, which may suggest a greater overall regenerative potential in the muscle. These findings suggest that exercise intensity may be an important factor in offsetting age and disease-related muscle atrophy in HFpEF. Importantly, studies show that sarcopenia and/or sarcopenic obesity are associated with worse exercise capacity in older HFpEF patients.7 As such, maintaining or increasing lean body mass with ET modalities such as HIIT or resistance training may contribute to improved exercise tolerance in HFpEF.The favorable improvements in molecular markers of skeletal muscle oxidative capacity and atrophy at 3 months were not maintained at 12 months. These results are in accord with the main findings of the Optimex trial,13 which found that both MCT and HIIT led to significant improvements in VO2peak at 3 months with supervised ET, but these beneficial effects were lost during the subsequent 9 months of home-based ET due to lower adherence with ET. Despite the proven efficacy of ET for improving exercise tolerance and quality of life in HFpEF, long-term compliance still remains a critical, unsolved problem that needs to be addressed by future research.In summary, the current study by Winzer et al12 is the first study to show that 3 months of ET increased skeletal muscle oxidative capacity and satellite cells and reduced molecular markers of muscle atrophy in HFpEF. These results suggest that efforts to develop new therapies for patients with HFpEF, particularly for their severe exercise intolerance, should focus on modifying skeletal muscle structure and function. In that regard, the present results provide several potential specific therapeutic targets.Article InformationSources of FundingDr Kitzman is supported in part by National Institutes of Health grants R01AG18915, R01AG045551, P30AG021332, U01HL160272, U01 AG076928, and U24AG059624 and the Kermit G. Phillips Endowed Chair in Cardiovascular Medicine.Disclosures Dr Kitzman reported receiving honoraria outside the present study as a consultant for Bayer, Corvia Medical, Boehringer Ingelheim, NovoNordisk, AstraZeneca, Novartis, and Rivus, grant funding outside the present study from Novartis, Bayer, NovoNordisk, and AstraZeneca, and stock ownership in Gilead Sciences. The other author reported no conflicts.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.Correspondence to: Dalane W. Kitzman, MD, Sections on Cardiovascular Medicine and Geriatrics/Gerontology, Kermit Glenn Phillips II Chair in Cardiovascular Medicine, Wake Forest School of Medicine, Medical Center Blvd, Winston-Salem, NC 27157-1045. Email dkitzman@wakehealth.eduReferences1. Tsao CW, Aday AW, Almarzooq ZI, Alonso A, Beaton AZ, Bittencourt MS, Boehme AK, Buxton AE, Carson AP, Commodore-Mensah Y, et al. Heart disease and stroke statistics-2022 update: a report from the American Heart Association.Circulation. 2022; 145:e153–e639. doi: 10.1161/CIR.0000000000001052LinkGoogle Scholar2. Haykowsky MJ, Brubaker PH, John JM, Stewart KP, Morgan TM, Kitzman DW. Determinants of exercise intolerance in elderly heart failure patients with preserved ejection fraction.J Am Coll Cardiol. 2011; 58:265–274. doi: 10.1016/j.jacc.2011.02.055CrossrefMedlineGoogle Scholar3. Nadruz W, West E, Sengeløv M, Santos M, Groarke JD, Forman DE, Claggett B, Skali H, Shah AM. prognostic value of cardiopulmonary exercise testing in heart failure with reduced, midrange, and preserved ejection fraction.J Am Heart Assoc. 2017; 6:e006000. doi: 10.1161/JAHA.117.006000LinkGoogle Scholar4. Borlaug BA. Evaluation and management of heart failure with preserved ejection fraction.Nat Rev Cardiol. 2020; 17:559–573. doi: 10.1038/s41569-020-0363-2CrossrefMedlineGoogle Scholar5. Fukuta H, Goto T, Wakami K, Ohte N. 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. 2016; 23:78–85. doi: 10.1177/2047487314564729CrossrefMedlineGoogle Scholar6. Dhakal BP, Malhotra R, Murphy RM, Pappagianopoulos PP, Baggish AL, Weiner RB, Houstis NE, Eisman AS, Hough SS, Lewis GD. Mechanisms of exercise intolerance in heart failure with preserved ejection fraction: the role of abnormal peripheral oxygen extraction.Circ Heart Fail. 2015; 8:286–294. doi: 10.1161/CIRCHEARTFAILURE.114.001825LinkGoogle Scholar7. Haykowsky MJ, Brubaker PH, Morgan TM, Kritchevsky S, Eggebeen J, Kitzman DW. Impaired aerobic capacity and physical functional performance in older heart failure patients with preserved ejection fraction: role of lean body mass.J Gerontol A Biol Sci Med Sci. 2013; 68:968–975. doi: 10.1093/gerona/glt011CrossrefMedlineGoogle Scholar8. Kitzman DW, Nicklas B, Kraus WE, Lyles MF, Eggebeen J, Morgan TM, Haykowsky M. Skeletal muscle abnormalities and exercise intolerance in older patients with heart failure and preserved ejection fraction.Am J Physiol Heart Circ Physiol. 2014; 306:H1364–H1370. doi: 10.1152/ajpheart.00004.2014CrossrefMedlineGoogle Scholar9. Molina AJ, Bharadwaj MS, Van Horn C, Nicklas BJ, Lyles MF, Eggebeen J, Haykowsky MJ, Brubaker PH, Kitzman DW. Skeletal muscle mitochondrial content, oxidative capacity, and mfn2 expression are reduced in older patients with heart failure and preserved ejection fraction and are related to exercise intolerance.JACC Heart Fail. 2016; 4:636–645. doi: 10.1016/j.jchf.2016.03.011CrossrefMedlineGoogle Scholar10. Fu TC, Yang NI, Wang CH, Cherng WJ, Chou SL, Pan TL, Wang JS. Aerobic interval training elicits different hemodynamic adaptations between heart failure patients with preserved and reduced ejection fraction.Am J Phys Med Rehabil. 2016; 95:15–27. doi: 10.1097/PHM.0000000000000312CrossrefMedlineGoogle Scholar11. Haykowsky MJ, Brubaker PH, Stewart KP, Morgan TM, Eggebeen J, Kitzman DW. Effect of endurance training on the determinants of peak exercise oxygen consumption in elderly patients with stable compensated heart failure and preserved ejection fraction.J Am Coll Cardiol. 2012; 60:120–128. doi: 10.1016/j.jacc.2012.02.055CrossrefMedlineGoogle Scholar12. Winzer EB, Augstein A, Schauer A, Mueller S, Fischer-Schaepmann T, Goto K, Hommel J, van Craenebroeck EM, Wisloff U, Pieske B, et al. Impact of different training modalities on molecular alterations in skeletal muscle of HFpEF patients: a substudy of the Optimex trial.Circ Heart Fail. 2022; 15:917–930. doi: 10.1161/CIRCHEARTFAILURE.121.009124.LinkGoogle Scholar13. Mueller S, Winzer EB, Duvinage A, Gevaert AB, Edelmann F, Haller B, Pieske-Kraigher E, Beckers P, Bobenko A, Hommel J, et al. Effect of high-intensity interval training, moderate continuous training, or guideline-based physical activity advice on peak oxygen consumption in patients with heart failure with preserved ejection fraction: a randomized clinical trial.JAMA. 2021; 325:542–551. doi: 10.1001/jama.2020.26812CrossrefMedlineGoogle Scholar14. Kitzman DW, Brubaker PH, Herrington DM, Morgan TM, Stewart KP, Hundley WG, Abdelhamed A, Haykowsky MJ. 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. 2013; 62:584–592. doi: 10.1016/j.jacc.2013.04.033CrossrefMedlineGoogle Scholar15. Lee JF, Barrett-O'Keefe Z, Garten RS, Nelson AD, Ryan JJ, Nativi JN, Richardson RS, Wray DW. Evidence of microvascular dysfunction in heart failure with preserved ejection fraction.Heart. 2016; 102:278–284. doi: 10.1136/heartjnl-2015-308403CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsRelated articlesImpact of Different Training Modalities on Molecular Alterations in Skeletal Muscle of Patients With Heart Failure With Preserved Ejection Fraction: A Substudy of the OptimEx TrialEphraim B. Winzer, et al. Circulation: Heart Failure. 2022;15 October 2022Vol 15, Issue 10 Advertisement Article InformationMetrics © 2022 American Heart Association, Inc.https://doi.org/10.1161/CIRCHEARTFAILURE.122.010003PMID: 36200441 Originally publishedOctober 6, 2022 KeywordsEditorialsmitochondriaheart failure, preserved ejection fractioncardiorespiratory fitnessmuscular atrophyhigh-intensity interval trainingexercise trainingPDF download Advertisement SubjectsHeart FailureRehabilitation