Vol 28, No 3 (2021)
Original Article
Published online: 2020-10-26
Iron status, catabolic/anabolic balance, and skeletal muscle performance in men with heart failure with reduced ejection fraction
1
, 1, 2, 2, 2, 2, 1, 1
, 1, 2, 2, 2, 2, 1, 1
Abstract
Background: Metabolic derangements related to tissue energetics constitute an important pathophysiological feature of heart failure. We investigated whether iron deficiency and catabolic/anabolic imbalance contribute to decreased skeletal muscle performance in men with heart failure with reduced ejection fraction (HFrEF), and whether these pathologies are related to each other.
Methods: We comprehensively examined 23 men with stable HFrEF (median age [interquartile range]: 63 [59–66] years; left ventricular ejection fraction: 28 [25–35]%; New York Heart Association class I/II/III: 17/43/39%). We analyzed clinical characteristics, iron status, hormones, strength and fatigability of forearm flexors and quadriceps (surface electromyography), and exercise capacity (6-minute walking test).
Results: None of the patients had anemia whereas 8 were iron-deficient. Flexor carpi radialis fatigability correlated with lower reticulocyte hemoglobin content (CHR, p < 0.05), and there was a trend towards greater fatigability in patients with higher body mass index and lower serum ferritin (both p < 0.1). Flexor carpi ulnaris fatigability correlated with lower serum iron and CHR (both p < 0.05). Vastus medialis fatigability was related to lower free and bioavailable testosterone (FT and BT, respectively, both p < 0.05), and 6-minute walking test distance was shorter in patients with higher cortisol/FT and cortisol/BT ratio (both p < 0.05). Lower ferritin and transferrin saturation correlated with lower percentage of FT and BT. Men with HFrEF and iron deficiency had higher total testosterone, but lower percentage of FT and BT.
Conclusions: Iron deficiency correlates with lower bioactive testosterone in men with HFrEF. These two pathologies can both contribute to decreased skeletal muscle performance in such patients.
Keywords: heart failureanabolic hormonesiron statusskeletal musclesexercise capacity
References
- Neubauer S. The failing heart--an engine out of fuel. N Engl J Med. 2007; 356(11): 1140–1151.
- Ingwall JS. Energy metabolism in heart failure and remodelling. Cardiovasc Res. 2009; 81(3): 412–419.
- Mettauer B, Zoll J, Garnier A, et al. Heart failure: a model of cardiac and skeletal muscle energetic failure. Pflugers Arch. 2006; 452(6): 653–666.
- Bayeva M, Gheorghiade M, Ardehali H. Mitochondria as a therapeutic target in heart failure. J Am Coll Cardiol. 2013; 61(6): 599–610.
- Anker SD, Chua TP, Ponikowski P, et al. Hormonal changes and catabolic/anabolic imbalance in chronic heart failure and their importance for cardiac cachexia. Circulation. 1997; 96(2): 526–534.
- Anker SD, Clark AL, Kemp M, et al. Tumor necrosis factor and steroid metabolism in chronic heart failure: possible relation to muscle wasting. J Am Coll Cardiol. 1997; 30(4): 997–1001.
- Jankowska EA, Biel B, Majda J, et al. Anabolic deficiency in men with chronic heart failure: prevalence and detrimental impact on survival. Circulation. 2006; 114(17): 1829–1837.
- Coats AJ, Clark AL, Piepoli M, et al. Symptoms and quality of life in heart failure: the muscle hypothesis. Br Heart J. 1994; 72(2 Suppl): S36–S39.
- Jankowska EA, von Haehling S, Anker SD, et al. Iron deficiency and heart failure: diagnostic dilemmas and therapeutic perspectives. Eur Heart J. 2013; 34(11): 816–829.
- Jankowska EA, Tkaczyszyn M, Kalicińska E, et al. Testosterone deficiency in men with heart failure: pathophysiology and its clinical, prognostic and therapeutic implications. Kardiol Pol. 2014; 72(5): 403–409.
- Ponikowski P, Voors AA, Anker SD, et al. 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 J Heart Fail. 2016; 18(8): 891–975.
- Blanc B, Finch CA, Hallberg L, et al. Nutritional anaemias. Report of a WHO scientific group. WHO Tech Rep Ser. 1968; 405: 1–40.
- Levey AS, Bosch JP, Lewis JB, et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med. 1999; 130(6): 461–470.
- Vermeulen A, Verdonck L, Kaufman JM. A critical evaluation of simple methods for the estimation of free testosterone in serum. J Clin Endocrinol Metab. 1999; 84(10): 3666–3672.
- Węgrzynowska-Teodorczyk K, Siennicka A, Josiak K, et al. Evaluation of Skeletal Muscle Function and Effects of Early Rehabilitation during Acute Heart Failure: Rationale and Study Design. Biomed Res Int. 2018; 2018: 6982897.
- Byrne CA, Lyons GM, Donnelly AE, et al. Rectus femoris surface myoelectric signal cross-talk during static contractions. J Electromyogr Kinesiol. 2005; 15(6): 564–575.
- Zizola C, Schulze PC. Metabolic and structural impairment of skeletal muscle in heart failure. Heart Fail Rev. 2013; 18(5): 623–630.
- Clark AL, Poole-Wilson PA, Coats AJ. Exercise limitation in chronic heart failure: central role of the periphery. J Am Coll Cardiol. 1996; 28(5): 1092–1102.
- Wilson JR, Mancini DM, Simson M. Detection of skeletal muscle fatigue in patients with heart failure using electromyography. Am J Cardiol. 1992; 70(4): 488–493.
- Buller NP, Jones D, Poole-Wilson PA. Direct measurement of skeletal muscle fatigue in patients with chronic heart failure. Br Heart J. 1991; 65(1): 20–24.
- Harridge SD, Magnusson G, Gordon A. Skeletal muscle contractile characteristics and fatigue resistance in patients with chronic heart failure. Eur Heart J. 1996; 17(6): 896–901.
- Dunnigan A, Staley NA, Smith SA, et al. Cardiac and skeletal muscle abnormalities in cardiomyopathy: comparison of patients with ventricular tachycardia or congestive heart failure. J Am Coll Cardiol. 1987; 10(3): 608–618.
- Minotti JR, Pillay P, Chang L, et al. Neurophysiological assessment of skeletal muscle fatigue in patients with congestive heart failure. Circulation. 1992; 86(3): 903–908.
- Minotti JR, Christoph I, Oka R, et al. Impaired skeletal muscle function in patients with congestive heart failure. Relationship to systemic exercise performance. J Clin Invest. 1991; 88(6): 2077–2082.
- Josiak K, Jankowska EA, Piepoli MF, et al. Skeletal myopathy in patients with chronic heart failure: significance of anabolic-androgenic hormones. J Cachexia Sarcopenia Muscle. 2014; 5(4): 287–296.
- Stugiewicz M, Tkaczyszyn M, Kasztura M, et al. The influence of iron deficiency on the functioning of skeletal muscles: experimental evidence and clinical implications. Eur J Heart Fail. 2016; 18(7): 762–773.
- Herbst KL, Bhasin S. Testosterone action on skeletal muscle. Curr Opin Clin Nutr Metab Care. 2004; 7(3): 271–277.
- Sato K, Iemitsu M, Aizawa K, et al. Testosterone and DHEA activate the glucose metabolism-related signaling pathway in skeletal muscle. Am J Physiol Endocrinol Metab. 2008; 294(5): E961–E968.
- Beard JL. Iron biology in immune function, muscle metabolism and neuronal functioning. J Nutr. 2001; 131(2S-2): 568S–579S; discussion 580S.
- Haas JD, Brownlie T. Iron deficiency and reduced work capacity: a critical review of the research to determine a causal relationship. J Nutr. 2001; 131(2S-2): 676S–688S; discussion 688S.
- Melenovsky V, Hlavata K, Sedivy P, et al. Skeletal Muscle Abnormalities and Iron Deficiency in Chronic Heart Failure. Circ Heart Fail. 2018; 11(9): e004800.
- Tkaczyszyn M, Drozd M, Węgrzynowska-Teodorczyk K, et al. Depleted iron stores are associated with inspiratory muscle weakness independently of skeletal muscle mass in men with systolic chronic heart failure. J Cachexia Sarcopenia Muscle. 2018; 9(3): 547–556.
- Jankowska EA, Filippatos G, Ponikowska B, et al. Reduction in circulating testosterone relates to exercise capacity in men with chronic heart failure. J Card Fail. 2009; 15(5): 442–450.
- Dziegala M, Josiak K, Kasztura M, et al. Iron deficiency as energetic insult to skeletal muscle in chronic diseases. J Cachexia Sarcopenia Muscle. 2018; 9(5): 802–815.
- Anker SD, Comin Colet J, Filippatos G, et al. FAIR-HF Trial Investigators. Ferric carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med. 2009; 361(25): 2436–2448.
- Toma M, McAlister FA, Coglianese EE, et al. Testosterone supplementation in heart failure: a meta-analysis. Circ Heart Fail. 2012; 5(3): 315–321.
- Charles-Edwards G, Amaral N, Sleigh A, et al. Effect of Iron Isomaltoside on Skeletal Muscle Energetics in Patients With Chronic Heart Failure and Iron Deficiency. Circulation. 2019; 139(21): 2386–2398.
- Doehner W, Frenneaux M, Anker SD. Metabolic impairment in heart failure: the myocardial and systemic perspective. J Am Coll Cardiol. 2014; 64(13): 1388–1400.
- Anker SD, Rauchhaus M. Heart failure as a metabolic problem. Eur J Heart Fail. 1999; 1(2): 127–131.
- van der Wal HH, Grote Beverborg N, Dickstein K, et al. Iron deficiency in worsening heart failure is associated with reduced estimated protein intake, fluid retention, inflammation, and antiplatelet use. Eur Heart J. 2019; 40(44): 3616–3625.
- Murphy L, Gray A, Joyce E. Anabolism to catabolism: serologic clues to nutritional status in heart failure. Curr Heart Fail Rep. 2019; 16(5): 189–200.
- Sandek A, Bauditz J, Swidsinski A, et al. Altered intestinal function in patients with chronic heart failure. J Am Coll Cardiol. 2007; 50(16): 1561–1569.
- Sandek A, Rauchhaus M, Anker SD, et al. The emerging role of the gut in chronic heart failure. Curr Opin Clin Nutr Metab Care. 2008; 11(5): 632–639.
- Rahman A, Jafry S, Jeejeebhoy K, et al. Malnutrition and Cachexia in Heart Failure. JPEN J Parenter Enteral Nutr. 2016; 40(4): 475–486.
- Sciatti E, Lombardi C, Ravera A, et al. Nutritional deficiency in patients with heart failure. Nutrients. 2016; 8(7): 442.
- van Veldhuisen DJ, Anker SD, Ponikowski P, et al. Anemia and iron deficiency in heart failure: mechanisms and therapeutic approaches. Nat Rev Cardiol. 2011; 8(9): 485–493.
- Moliner P, Enjuanes C, Tajes M, et al. Association between norepinephrine levels and abnormal iron status in patients with chronic heart failure: is iron deficiency more than a comorbidity? J Am Heart Assoc. 2019; 8(4): e010887.
- Anker SD, Sharma R. The syndrome of cardiac cachexia. Int J Cardiol. 2002; 85(1): 51–66.
- Guo W, Bachman E, Li M, et al. Testosterone administration inhibits hepcidin transcription and is associated with increased iron incorporation into red blood cells. Aging Cell. 2013; 12(2): 280–291.
- Latour C, Kautz L, Besson-Fournier C, et al. Testosterone perturbs systemic iron balance through activation of epidermal growth factor receptor signaling in the liver and repression of hepcidin. Hepatology. 2014; 59(2): 683–694.
