You are here

Article Text

Article menu

Download PDFPDF

Congenital heart disease
Original research
Iron deficiency in patients with a Fontan circulation and its impact on exercise capacity
  1. Gaston van Hassel1,
  2. Sean C S Rivrud2,
  3. Frank J Timmerman2,
  4. Peter van der Meer2,
  5. Elke S Hoendermis2,
  6. Eryn T Liem1,
  7. Rolf M F Berger1 and
  8. Joost P van Melle2
  1. 1Center for Congential Heart Diseases, Department of Paediatric Cardiology, Beatrix Children's Hospital, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
  2. 2Department of Cardiology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands
  1. Correspondence to Dr Gaston van Hassel; g.van.hassel{at}umcg.nl

Abstract

Background Iron deficiency (ID) has been reported in patients with congenital heart disease. There is, however, a scarcity of data on its prevalence in patients with a Fontan circulation. The aim of this study is to investigate the prevalence of ID in Fontan patients and to investigate the association between ID and exercise capacity in this population.

Methods and results Blood count and haematological parameters were determined in plasma of 61 Fontan patients (51% female, mean age 29±9 years). ID was defined as transferrin saturation (TSAT) ≤19.8%. The prevalence of ID was 36% (22/61 patients). Especially among women, the diagnosis of ID was highly prevalent (52%) despite normal haemoglobin levels (153.7±18.4 g/L). Mean ferritin levels were 98±80 µg/L and mean TSAT levels were 22%±12%. Cardiopulmonary exercise testing was performed in 46 patients (75%). Patients with ID had a lower peak oxygen uptake (V̇O2peak) (1397±477 vs 1692±530 mL/min; p=0.039), although this relationship was confounded by sex. The presence of ID increased the likelihood of not achieving a respiratory exchange ratio (RER) ≥1.1 by 5-fold (p=0.035).

Conclusion ID is highly prevalent among patients with a Fontan circulation. V̇O2peak is lower in patients with ID. Fontan patients with ID are less likely to achieve an RER≥1.1 during cardiopulmonary exercise testing.

  • Heart Defects, Congenital
  • Fontan Procedure
  • Congenital Abnormalities

Data availability statement

Data are available on reasonable request. Data are available on reasonable request. The data that support the findings of this study are available from the corresponding author, GvH, on reasonable request.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/openhrt-2024-002693

Statistics from Altmetric.com

    Request Permissions

    If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • Iron deficiency is prevalent in patients with congestive heart failure and is strongly associated with a decreased exercise tolerance.

    WHAT THIS STUDY ADDS

    • Iron deficiency is highly prevalent in patients with a Fontan circulation.

    • Peak oxygen uptake is lower in Fontan patients with iron deficiency.

    • The presence of iron deficiency increases the risk of not achieving a respiratory exchange ratio ≥1.1 during cardiopulmonary exercise testing.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • Iron deficiency is associated with poor results during cardiopulmonary exercise testing. Patients with a Fontan circulation and iron deficiency could potentially benefit from iron suppletion therapy. However, further research on this topic is required.

    Introduction

    A Fontan circulation is the treatment of choice for patients born with a functional univentricular heart when biventricular repair is not possible.1 In this circulation, the caval veins are directly connected to the pulmonary artery, thereby bypassing the subpulmonary ventricle. As a result, the Fontan circulation is characterised by chronically elevated systemic venous pressures and a decreased cardiac output.1 Ongoing improvements in perioperative care and surgical techniques have significantly improved prognosis for patients born with a univentricular circulation.2 Nevertheless, after Fontan completion, these patients are exposed to a myriad of long-term complications and comorbidities, including a significantly impaired exercise capacity, which is a strong predictor of morbidity and mortality in this population.3

    Iron deficiency (ID) is a highly prevalent comorbidity in chronic heart failure (CHF), with a reported prevalence ranging from 40% to 85%.4 5 In CHF patients, ID is independently associated with reduced exercise capacity, recurrent HF hospitalisation and mortality.6 ID is also a recognised comorbidity in patients with congenital heart disease.7 The exact prevalence of ID in patients with a Fontan circulation, however, remains largely unexplored, despite the presence of several predisposing risk factors for the development of ID (eg, malnutrition, gastrointestinal malabsorption, chronic use of anticoagulants and/or chronic subclinical inflammation).8–10 The relationship between ID and exercise tolerance has been extensively studied in patients with CHF, a clinical syndrome that shares specific characteristics with the Fontan circulation/Fontan failure, including chronically elevated systemic venous pressures, decreased cardiac output and, maybe more importantly, chronic subclinical inflammation.6 8 11 However, despite these similar characteristics, little is known about the relationship between ID and exercise tolerance in patients with a Fontan circulation. Therefore, the aim of this study is to investigate the prevalence of ID in patients with a Fontan circulation and its association with exercise performance.

    Methods

    Study population

    In this retrospective study, we included Fontan patients followed at the cardiology outpatient clinic of the University Medical Centre Groningen, The Netherlands. Briefly, Fontan patients ≥10 years of age, undergo a regular and standardised follow-up, including cardiopulmonary exercise testing (CPET), cardiac MRI, echocardiography and venepuncture for laboratory measurements every 2 years to establish attrition rates. Written consent was acquired from all patients and/or their parents. Demographic, clinical and cardiac related characteristics were extracted from patient records.

    Haematological parameters

    All included patients had laboratory measurements of iron, ferritin, transferrin, transferrin saturation (TSAT) and total iron binding capacity (IBC), as part of the established institutional follow-up protocol. In order to account for potential misclassification of ID as a result of continuous low-grade inflammation in patients with a Fontan circulation, we defined ID as TSAT<19.8%, as determined by Grote Beverborg et al.5 8 Anaemia was defined as haemoglobin (Hb) <120 g/L (females) and <130 g/L (males).12

    Cardiopulmonary exercise test

    CPET was performed on a treadmill using a Bruce protocol or modified Bruce protocol. Oxygen uptake was measured by breath-by-breath gas analysis. The respiratory exchange ratio (RER) was calculated as the ratio between carbon dioxide production and oxygen uptake (V̇O2). A peak RER value ≥1.1 is widely accepted as an excellent exercise effort.13 Peak V̇O2 (V̇O2peak) was calculated as the mean of the of the two highest V̇O2 measurements during exercise.

    Statistical analyses

    Baseline characteristics are presented as mean±SD, median (Q1–Q3), or number (percentage) depending on distribution. Normality of the characteristics was evaluated by visual inspection of histogram and Q-Q plots. Patients with and without ID were compared using the χ2 test for categorical variables and a Mann-Whitney U test or an unpaired t-test for continuous variables, depending on distribution.

    To analyse the correlation between ID and CPET parameters, we included only the patients in whom the date of venepuncture and the date of CPET were within a time span of 12 months. This selection comprised 46 patients (75%). To test the possibility of a selection bias, patients with and without CPET were compared. Sensitivity analyses were consecutively performed with the time intervals between CPET and venepuncture set at a maximum of 6 months and 1 month, respectively.

    Differences in CPET parameters between patients with and without ID were analysed using an unpaired t-test or Mann-Whitney U test and visualised using boxplots. Additional analyses, consisting solely of patients with an RER≥1.1, were also performed.

    Comparison of patients with an RER≥1.1 and <1.1, was performed using an unpaired t-test, a Mann-Whitney U test or χ2 test if appropriate. Univariable and multivariable logistic regression analysis was performed to find predictors for an RER<1.1. Because of the limited number of patients reaching an RER<1.1, only age, sex and ID were included in multivariable models.

    The R statistical software (V.4.2.2, Vienna, Austria) was used for analyses designing the figures. A two-sided p<0.05 was considered to indicate statistical significance.

    Results

    Characteristics

    Patient characteristics are presented according to the prevalence of ID in table 1. We included 61 patients with a mean age of 29±9 years, of whom 51% were female. The most frequent underlying cardiac diagnosis was tricuspid atresia (43%), followed by double inlet left ventricle (26%). The majority of the study population had a left ventricular dominance (85%) and was palliated with a total cavopulmonary connection, using the right atrial appendage. Mean Hb levels were 153.7±18.4 g/L, haematocrit (Ht) was 0.46±0.05 L/L and mean corpuscular volume was 89.9±4.8 fL. Only two individuals (3%) in this series were anaemic. Mean serum iron level was 14.2±6.1 µmol/L, ferritin level was 98±80 µg/L, TSAT percentage was 22%±12% and IBC was 70±17 µmol/L. 22 of these patients (36%) had a TSAT≤19.8% and were classified as having ID. Patients with ID were more often female. In addition, Hb, ferritin concentrations and TSAT were lower in patients with ID as compared with patients without ID. No patients had iron suppletion/maintenance therapy.

    View this table:
    Table 1

    Baseline patient characteristics according to the prevalence of ID

    Cardiopulmonary exercise test

    46 patients underwent CPET within 12 months of the laboratory assessment. Patients who did not undergo CPET were more often female with on average lower Hb and Ht levels. The prevalence of ID was comparable between those who did undergo CPET and those who did not (data not shown). Table 2 summarises CPET parameters. Overall, mean ± SD V̇O2peak was 1570±524 mL/min, resulting in a mean percentage of predicted V̇O2peak of 54%±13%. The mean RER that was reached was 1.06±0.12. Maximum attained workload (median) was 201 (156–308) Watt. Patients with ID had a lower V̇O2peak (1397±477 vs 1692±530 mL/min; p=0.039; figure 1). The relationship between V̇O2peak and ID lost significance when adjusted for age and sex (β =−109, p=0.4). V̇O2peak, as percentage of predicted, did not differ significantly between both groups (p=0.6), whereas workload tended to be lower in patients with ID (p=0.067).

    View this table:
    Table 2

    Cardiopulmonary tests results according to prevalence of ID

    Figure 1
    Figure 1

    V̇O2peak according to the presence of iron deficiency (ID). V̇O2peak, peak oxygen uptake.

    29 patients (63%) did not achieve an RER≥1.1. Mean RER was lower in patients with ID as compared with patients without ID (1.02±0.09 vs 1.09±0.13; p=0.025; figure 2). Additionally, we observed a lower prevalence of RER≥1.1 in patients with ID. Sensitivity analysis showed comparable results for time intervals of 6 months (N=28; p=0.023) and 1 month (N=17; p=0.3), although the latter did not reach statistical significance.

    Figure 2
    Figure 2

    Respiratory exchange ratio (RER) according to the presence of iron deficiency (ID).

    Patient characteristics according RER groups are shown in table 3. Patients with an RER<1.1 had a lower TSAT than those with an RER≥1.1 (18% (6%–23%) vs 25% (24%–31%), p=0.005). Additionally, we observed a higher prevalence of ID in patients who did not reach RER≥1.1 (p=0.013).

    View this table:
    Table 3

    Patient characteristics of those who underwent CPET according to RER groups

    Univariable logistic regression analyses showed that ID was associated with a more than 5-fold increased risk of not achieving a peak RER≥1.1 (OR 5.47, 95% CI 1.49 to 29.96, p=0.018; table 4). Adjusted for age and sex, the presence of ID remained independently associated with a 5.1-fold (OR 5.09, 95% CI 1.22 to 27.23, p=0.035; table 5) increased rate of not achieving RER≥1.1.

    View this table:
    Table 4

    Univariable logistic regression for RER<1.1

    View this table:
    Table 5

    Multivariable logistic regression for RER<1.1

    Discussion

    The present study showed a high prevalence of ID (36%) in a contemporary cohort of patients with a Fontan circulation. Of note, more than half of the female Fontan patients (52%) turned out to be iron deficient. ID was associated with a lower peak VO2, although this relationship was confounded by sex. Patients with ID were less likely to achieve an RER≥1.1 as compared with those without ID.

    The prevalence of ID in Fontan patients has not been previously reported. The prevalence of 36%, found in this contemporary cohort of Fontan patients, is lower than the prevalence of ID reported in patients with CHF, but significantly higher than that in the general Dutch population, in which it is approximately 7%.5 14 The definition of ID has been subject to debate.5 In routine clinical practice, ID is often diagnosed through a combination of both ferritin and TSAT (ferritin <100 µg/L or ferritin 100–300 µg/L and TSAT<20%).5 However, ferritin, an acute phase protein, typically rises in inflammatory conditions and in the presence of liver disease, both of which are common in patients with a Fontan circulation.8 15 16 We believe that the use of ferritin may, therefore, underdiagnose ID in patients with a Fontan circulation, analogous to patients with HF. Therefore, in the current study, we defined ID as TSAT<19.8%, as established previously by Grote Beverborg et al.5 Fontan patients are subject to various circumstances that can induce ID. First, a state of continuous low-grade inflammation has been reported to be present in many Fontan patients.8 Inflammation leads to increased concentrations of hepcidin, which inhibits the ferroportin mediated iron efflux from macrophages, hepatocytes and duodenal erythrocytes. This inhibition limits the iron supply to blood plasma, resulting in ID.15 Second, hepatic congestion as a result of elevated central venous pressures has been found to also upregulate hepcidin expression, thereby further exacerbating ID.9 Lastly, chronic high systemic venous pressures, an obligate consequence of the Fontan circulation, may lead to gastrointestinal protein and blood loss and malabsorption, which can further significantly contribute to ID by reducing the overall availability of iron.10

    Until recently, ID was considered clinically relevant only in the setting of anaemia. However, studies in CHF patients have underscored the importance of ID independent of anaemia. In these studies, ID was found to be strongly associated with impaired exercise tolerance, quality of life and mortality, irrespective of Hb levels.11 17 In contrast, not much is known about the impact of ID on exercise tolerance and outcome in patients with a Fontan circulation. To our knowledge, the sole study investigating haematological parameters in a cohort of Fontan patients was reported by Tomkiewicz-Pajak et al. These authors, however, used an indirect measure of ID, namely red cell distribution width (RDW) and found a negative correlation between RDW and exercise tolerance.18 In the current study, using a more direct characterisation of ID, patients with ID showed a significant lower exercise tolerance, as defined by V̇O2peak. However, these findings are most likely a reflection of the sex differences between the patients with and without ID, as we did not find a significant relationship between ID and V̇O2peak when adjusted for age and sex.

    Low exercise tolerance is an important predictor of morbidity and mortality in patients with a Fontan circulation.3 However, many patients with a Fontan circulation are unable to reach the established minimum criterion for peak effort during CPET, namely an RER≥1.1.13 In this study, we observed that only 37% of the Fontan patients who underwent CPET were able to achieve an RER≥1.1. This is in line with previous studies in Fontan patients, but it is significantly lower compared with patients with CHF (74%).19–23 Although insufficiently understood, several factors are known to influence RER during exercise including exercise duration, exercise intensity, training status, sex and mitochondrial enzyme activity.24 In patients with a Fontan circulation, which is characterised by the lack of a subpulmonary ventricle, the peripheral muscle pump is key in promoting venous return. Therefore, their decreased skeletal muscle mass—most likely due to a sedentary lifestyle—but also intrinsic muscle abnormalities may play a role in the inability to reach an RER≥1.1.25

    In the current study, we found that the majority of patients who did not achieve an RER≥1.1 had ID. Previous in vitro and animal studies have demonstrated that cellular iron depletion directly affects skeletal muscles by downregulation of mitochondrial protein levels and oxidative capacity.26 Additionally, in human cardiomyocytes, ID is shown to impair mitochondrial respiration, and to reduce contractility and relaxation.27 Building on these findings, Goedecke et al found that mitochondrial enzyme activity was one of the most important factors influencing RER during endurance exercise where higher enzyme activity was associated with a higher RER.28 Therefore, ID, also in the absence of overt anaemia, may lead to the inability to reach an RER≥1.1 due to a direct decrease in both cardiac and skeletal muscle function. Especially in Fontan patients with ID, a combination of reduced cardiac as well as skeletal muscle function will hamper exercise at higher intensities precluding the achievement of an RER≥1.1.

    Exercise capacity in patients with a Fontan circulation is a multifaceted endpoint, depending on many variables, both physiological as well as non-physiological. In the current study, we described that ID could be appreciated as one of these factors influencing exercise tolerance in patients with a Fontan circulation. In addition, based on the high prevalence of ID observed in a contemporary cohort of Fontan patients, one may speculate that administration of iron supplementation to Fontan patients—with ID—will improve exercise capacity, similar to patients with CHF.11 Although these findings, taken together, provide strong arguments for the implementation of iron supplementation in the treatment of ID in patients with a Fontan circulation, further research in the setting of a cross-sectional study or randomised controlled trial is warranted.

    Strengths and limitations

    Our study has several strengths and limitations that should be addressed. First, the investigation of the prevalence of ID in a cohort consisting solely of patients with a Fontan circulation and relating it to exercise capacity is unprecedented. Additionally, testing for iron metabolism parameters was performed as standard practice, which reduces the risk of selection bias for the investigation of ID in this population. We investigated the relationship between ID and exercise capacity in tests that took place within 12 months of each other. Preferably, we would have investigated this relationship in tests that took place within a 1-month timespan. However, only few patients underwent both tests within 1 month, thereby reducing power. Additionally, the use of multivariate analyses was limited due to the small cohort size and limited number patients with an RER≥1.1.

    Conclusion

    In conclusion, ID is highly prevalent in contemporary patients with a Fontan circulation. Peak V̇O2 is lower in patients with ID. The presence of ID was a strong independent predictor for not achieving an RER≥1.1 at CPET. The adverse effect of ID on muscle strength may play a role in reduced exercise capacity in Fontan patients. However, whether iron replacement therapy will improve exercise capacity in Fontan patients with ID requires further studies.

    Data availability statement

    Data are available on reasonable request. Data are available on reasonable request. The data that support the findings of this study are available from the corresponding author, GvH, on reasonable request.

    Ethics statements

    Patient consent for publication

    Ethics approval

    This study involves human participants and was approved by Medisch Etische Toetsingscommissie UMC Groningen (METc: 20122080). Participants gave informed consent to participate in the study before taking part.

    References

    1. ↵
      1. Gewillig M,
      2. Brown SC
      . The Fontan circulation after 45 years: update in physiology. Heart 2016;102:1081–6. doi:10.1136/heartjnl-2015-307467
      OpenUrlAbstract/FREE Full Text
    2. ↵
      1. Wolff D,
      2. van Melle JP,
      3. Ebels T, et al
      . Trends in mortality (1975-2011) after one- and two-stage Fontan surgery, including Bidirectional Glenn through Fontan completion. European Journal of Cardio-Thoracic Surgery 2014;45:602–9. doi:10.1093/ejcts/ezt461
      OpenUrlCrossRefPubMed
    3. ↵
      1. Diller G-P,
      2. Giardini A,
      3. Dimopoulos K, et al
      . Predictors of morbidity and mortality in contemporary Fontan patients: results from a multicenter study including cardiopulmonary exercise testing in 321 patients. Eur Heart J 2010;31:3073–83. doi:10.1093/eurheartj/ehq356
      OpenUrlCrossRefPubMedWeb of Science
    4. ↵
      1. McDonagh TA,
      2. Metra M,
      3. Adamo M, et al
      . ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2021;42:3599–726. doi:10.1093/eurheartj/ehab368
      OpenUrlCrossRefPubMed
    5. ↵
      1. Grote Beverborg N,
      2. Klip IjT,
      3. Meijers WC, et al
      . Definition of iron deficiency based on the gold standard of bone marrow iron staining in heart failure patients. Circ: Heart Failure 2018;11:1–11. doi:10.1161/CIRCHEARTFAILURE.117.004519
      OpenUrl
    6. ↵
      1. McDonagh TA,
      2. Metra M,
      3. Adamo M, et al
      . Focused update of the 2021 ESC guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J 2023;44:3627–39. doi:10.1093/eurheartj/ehad195
      OpenUrl
    7. ↵
      1. Martínez-Quintana E,
      2. Rodríguez-González F
      . Iron deficiency anemia detection from hematology parameters in adult congenital heart disease patients. Congenit Heart Dis 2013;8:117–23. doi:10.1111/j.1747-0803.2012.00708.x
      OpenUrl
    8. ↵
      1. Saraf A,
      2. De Staercke C,
      3. Everitt I, et al
      . Biomarker profile in stable Fontan patients ☆. International Journal of Cardiology 2020;305:56–62. doi:10.1016/j.ijcard.2020.01.012
      OpenUrl
    9. ↵
      1. Tim Goodnough L,
      2. Comin-Colet J,
      3. Leal-Noval S, et al
      . Management of anemia in patients with congestive heart failure. Am J Hematol 2017;92:88–93. doi:10.1002/ajh.24595
      OpenUrl
    10. ↵
      1. Vyas H,
      2. Driscoll DJ,
      3. Cetta F, et al
      . Gastrointestinal bleeding and protein-losing Enteropathy after the Fontan operation. Am J Cardiol 2006;98:666–7. doi:10.1016/j.amjcard.2006.03.049
      OpenUrlPubMed
    11. ↵
      1. Anker SD,
      2. Comin Colet J,
      3. Filippatos G, et al
      . Ferric Carboxymaltose in patients with heart failure and iron deficiency. N Engl J Med 2009;361:2436–48. doi:10.1056/NEJMoa0908355
      OpenUrlCrossRefPubMedWeb of Science
    12. ↵
      1. Ayerdem G,
      2. van Hassel G,
      3. Vinke JSJ, et al
      . Iron deficiency, with and without anaemia, across strata of kidney function in kidney transplant recipients. Nephrol Dial Transplant 2021;36:2342–4. doi:10.1093/ndt/gfab173
      OpenUrl
    13. ↵
      1. Guazzi M,
      2. Adams V,
      3. Conraads V, et al
      . Clinical recommendations for cardiopulmonary exercise testing data assessment in specific patient populations. Eur Heart J 2012;33:2917–27. doi:10.1093/eurheartj/ehs221
      OpenUrlCrossRefPubMedWeb of Science
    14. ↵
      1. Eisenga MF,
      2. De Jong MA,
      3. Van der Meer P, et al
      . Iron deficiency, elevated erythropoietin, fibroblast growth factor 23, and mortality in the general population of the Netherlands: A cohort study. PLoS Med 2019;16:e1002818. doi:10.1371/journal.pmed.1002818
    15. ↵
      1. Pasricha S-R,
      2. Tye-Din J,
      3. Muckenthaler MU, et al
      . Iron deficiency. The Lancet 2021;397:233–48. doi:10.1016/S0140-6736(20)32594-0
      OpenUrl
    16. ↵
      1. Gordon-Walker TT,
      2. Bove K,
      3. Veldtman G
      . Fontan-associated liver disease: A review. J Cardiol 2019;74:223–32. doi:10.1016/j.jjcc.2019.02.016
      OpenUrlCrossRefPubMed
    17. ↵
      1. Klip IT,
      2. Comin-Colet J,
      3. Voors AA, et al
      . Iron deficiency in chronic heart failure: an international pooled analysis. Am Heart J 2013;165:575–82. doi:10.1016/j.ahj.2013.01.017
      OpenUrlCrossRefPubMedWeb of Science
    18. ↵
      1. Tomkiewicz-Pajak L,
      2. Plazak W,
      3. Kolcz J, et al
      . Iron deficiency and hematological changes in adult patients after Fontan operation. J Cardiol 2014;64:384–9. doi:10.1016/j.jjcc.2014.02.021
      OpenUrl
    19. ↵
      1. Carey PM,
      2. Yeh H-W,
      3. Krzywda K, et al
      . Moderators of peak respiratory exchange ratio during exercise testing in children and adolescents with Fontan physiology. Cardiol Young 2023;33:2334–41. doi:10.1017/S1047951123000227
      OpenUrl
    20. ↵
      1. McCrindle BW,
      2. Zak V,
      3. Sleeper LA, et al
      . Laboratory measures of exercise capacity and ventricular characteristics and function are weakly associated with functional health status after Fontan procedure. Circulation 2010;121:34–42. doi:10.1161/CIRCULATIONAHA.109.869396
      OpenUrlAbstract/FREE Full Text
    21. ↵
      1. Chen C-A,
      2. Chen S-Y,
      3. Chiu H-H, et al
      . Prognostic value of Submaximal exercise data for cardiac morbidity in Fontan patients. Med Sci Sports Exerc 2014;46:10–5. doi:10.1249/MSS.0b013e31829f8326
      OpenUrlCrossRefPubMed
    22. ↵
      1. Paridon SM,
      2. Mitchell PD,
      3. Colan SD, et al
      . A cross-sectional study of exercise performance during the first 2 decades of life after the Fontan operation. J Am Coll Cardiol 2008;52:99–107. doi:10.1016/j.jacc.2008.02.081
      OpenUrlFREE Full Text
    23. ↵
      1. Mezzani A,
      2. Corrà U,
      3. Bosimini E, et al
      . Contribution of peak respiratory exchange ratio to peak Vo2 Prognostic reliability in patients with chronic heart failure and severely reduced exercise capacity. Am Heart J 2003;145:1102–7. doi:10.1016/S0002-8703(03)00100-5
      OpenUrlCrossRefPubMedWeb of Science
    24. ↵
      1. Rothschild JA,
      2. Kilding AE,
      3. Stewart T, et al
      . Factors influencing substrate oxidation during Submaximal Cycling: A Modelling analysis. Sports Med 2022;52:2775–95. doi:10.1007/s40279-022-01727-7
      OpenUrl
    25. ↵
      1. Cordina R,
      2. O’Meagher S,
      3. Gould H, et al
      . Skeletal muscle abnormalities and exercise capacity in adults with a Fontan circulation. Heart 2013;99:1530–4. doi:10.1136/heartjnl-2013-304249
      OpenUrlAbstract/FREE Full Text
    26. ↵
      1. Rensvold JW,
      2. Ong S-E,
      3. Jeevananthan A, et al
      . Complementary RNA and protein profiling identifies iron as a key regulator of mitochondrial Biogenesis. Cell Reports 2013;3:237–45. doi:10.1016/j.celrep.2012.11.029
      OpenUrl
    27. ↵
      1. Hoes MF,
      2. Grote Beverborg N,
      3. Kijlstra JD, et al
      . Iron deficiency impairs contractility of human cardiomyocytes through decreased mitochondrial function. Eur J Heart Fail 2018;20:910–9. doi:10.1002/ejhf.1154
      OpenUrlCrossRefPubMed
    28. ↵
      1. Goedecke JH,
      2. St Clair Gibson A,
      3. Grobler L, et al
      . Determinants of the variability in respiratory exchange ratio at rest and during exercise in trained athletes. Am J Physiol Endocrinol Metab 2000;279:E1325–34. doi:10.1152/ajpendo.2000.279.6.E1325
      OpenUrlCrossRefPubMedWeb of Science

    Footnotes

    • Contributors Research idea and study design: GvH, JPvM and RMFB. Data acquisition: GvH, SCSR, FJT, ESH, JPvM and RMFB. Data analysis/interpretation: GvH, SCSR, FJT, ESH, ETL and PvdM, RMFB and JPvM. Statistical analysis: GvH and SCSR. Manuscript writing: GvH, JPvM and RMFB. Manuscript review: GvH, SCSR, FJT, ESH, ETL, PvdM, RMFB and JPvM. Supervision or mentorship: JPvM and RMFB. Guarantor: RMFB. Each author contributed important intellectual content during manuscript drafting or revision accepts personal accountability for the authors own contributions, and agrees to ensure that questions pertaining to the accuracy or integrity of any portion of the work are appropriately investigated and resolved.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests RMFB: The University Medical Center Groningen contracts with Janssen, MSD and GSK for steering committee and advisory board committee activities of RMFB, outside the scope of this manuscript.

    • Provenance and peer review Not commissioned; externally peer reviewed.