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Resistance training improves cardiac output, exercise capacity and tolerance to positive airway pressure in Fontan physiology
IJCA-15425; No of Pages 9 International Journal of Cardiology xxx (2012) xxx–xxx
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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Resistance training improves cardiac output, exercise capacity and tolerance to positive airway pressure in Fontan physiology☆ Rachael L. Cordina a, b, Shamus O'Meagher a, b, Alia Karmali a, Caroline L. Rae c, d, Carsten Liess e, Graham J. Kemp f, Raj Puranik a, b, Nalin Singh g, h, David S. Celermajer a, b,⁎ a
Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia Department of Cardiology, Sydney Medical School, Sydney, Australia Neuroscience Research Australia, Sydney, Australia d Faculty of Medicine, University of New South Wales, Sydney, Australia e Philips Healthcare, Sydney, Australia f Departments of Musculoskeletal Biology and Magnetic Resonance and Image Analysis Research Centre, University of Liverpool, Liverpool, United Kingdom g Department of Aged Care, Royal Prince Alfred Hospital, Sydney, Australia h Department of Aged Care, Balmain Hospital, Sydney, Australia b c
a r t i c l e
i n f o
Article history: Received 9 August 2012 Accepted 7 October 2012 Available online xxxx Keywords: Congenital heart disease Single ventricle Fontan operation Cardiac rehabilitation Exercise training Cardiac function
a b s t r a c t Background: Subjects with Fontan-type circulation have no sub-pulmonary ventricle and thus depend exquisitely on the respiratory bellows and peripheral muscle pump for cardiac filling. We hypothesised that resistance training to augment the peripheral muscle pump might improve cardiac filling, reduce inspiratory-dependence of IVC return to the heart and thus improve exercise capacity and cardiac output on constant positive airway pressure (CPAP). Methods: Eleven Fontan subjects (32+/− 2 years, mean+/−SEM) had cardiac magnetic resonance imaging (MRI) and exercise testing (CPET); six underwent 20 weeks of high-intensity resistance training; others were non-exercising controls. After training, CPET was repeated. Four trainers had MRI with real-time flow measurement at rest, exercise and on CPAP in the trained state and following a 12-month detrain. Results: In the trained state, muscle strength increased by 43% (p =0.002), as did total muscle mass (by 1.94 kg, p=0.003) and peak VO2 (by 183 ml/min, p=0.02). After detraining, calf muscle mass and peak workload had fallen significantly (p b 0.03 for both) as did peak VO2 (2.72 vs. 2.18 l/min, pb 0.001) and oxygen pulse, a surrogate for SV (16% lower, p=0.005). Furthermore after detraining, SV on MRI decreased at rest (by 11 ml, p =0.01) and during moderate-intensity exercise (by 16 ml, p=0.04); inspiratory-dependent IVC blood return during exercise was 40% higher (p=0.02). On CPAP, cardiac output was lower in the detrained state (101 vs. 77 ml/s, p=0.03). Conclusions: Resistance muscle training improves muscle mass, strength and is associated with improved cardiac filling, stroke volume, exercise capacity and cardiac output on CPAP, in adults with Fontan-type circulation. Crown Copyright © 2012 Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction First described in 1971 by Fontan and Kreutzer [1] as a surgical option for patients with tricuspid atresia, the remarkable Fontan procedure is now commonly performed to palliate various forms of essentially single-ventricle congenital heart disease (CHD), with increasing numbers surviving to adulthood. The Fontan circuit, which functions without the sub-pulmonary ventricle as a power source to pump blood through the
☆ All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ⁎ Corresponding author at: Department of Cardiology, Royal Prince Alfred Hospital, Missenden Rd, Camperdown, NSW 2050, Australia. Tel.: +61 2 9515 6111; fax: +61 2 9550 6262. E-mail address: [email protected] (D.S. Celermajer).
lungs, relies heavily on the respiratory bellows to draw blood into the pulmonary vascular bed during inspiration [2]. As a consequence, cardiac output in these subjects falls during positive pressure ventilation [3]. Despite surgical advances in the Fontan operation there are important long-term consequences from living without a sub-pulmonary circulatory pump. Whilst subjects with a well-functioning Fontan-type circulation perform quite well during low-level day-to-day activities, they are generally limited during more intense levels of exercise; a major contributor to this limitation is reduced cardiac filling, due to the altered anatomy and physiology [4–7]. Even the normal heart cannot increase cardiac output more than a few percent without the aid of the periphery [8]. During upright exercise the peripheral pumping mechanism must overcome the effects of gravity to enable diastolic filling. At the onset of exercise stroke volume rises, by about the same volume as when a subject goes from supine to sitting [9]. This refilling of the ventricle is from blood mobilised from the
0167-5273/$ – see front matter. Crown Copyright © 2012 Published by Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2012.10.012
Please cite this article as: Cordina RL, et al, Resistance training improves cardiac output, exercise capacity and tolerance to positive airway pressure in Fontan physiology, Int J Cardiol (2012), http://dx.doi.org/10.1016/j.ijcard.2012.10.012
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lower extremities [10]. In addition, venous compliance in the leg has been shown in normal subjects to have a close negative correlation with calf surface area and muscle mass [11] and in the Fontan circulation the effects of gravity have been shown to adversely affect anterograde inferior vena caval (IVC) flow [12]. This suggests that an enhanced peripheral muscle mass and associated skeletal muscle pump could be especially important in those with Fontan physiology. We hypothesised that muscle resistance training to augment the peripheral muscle pump might improve cardiac filling and stroke volume in the Fontan circulation and reduce the inspiratory dependence of IVC blood return to the heart. For the same reasons, we postulated that resistance training might also improve exercise capacity and cardiac output during constant positive airway pressure (CPAP).
detrain period was added to the project for these 4 FBMR subjects, so that they could be analysed in both trained and detrained states. 2.3. Cardiopulmonary exercise testing CPET comprised a ramp-protocol cycle test on an electrically braked bicycle ergometer (Lode Corival; Lode BV, Groningen, The Netherlands). CPET method is described in detail elsewhere (see Online Supplement). Oxygen pulse, a surrogate for stroke volume during CPET, was calculated by dividing VO2 (oxygen uptake) by heart rate. Anaerobic threshold was calculated using the V-slope method, by a blinded observer [13]. Peak VO2 and peak workload were compared to predicted normal values [14]. Eighty percent of the untrained peak work (0.8 isotime) was calculated and important parameters were then compared at that workload. Delta values were calculated by subtracting the post-training (or in the case of non-trainers, post-control period) result from the baseline result. One training subject stopped his post-training CPET prematurely due to anxiety. At the point of cessation his physiologic parameters (such as heart rate, respiratory quotient and VO2) suggested he had not reached exhaustion and thus this subject's data were subsequently removed, from peak exercise data analysis only.
2. Methods 2.4. Body composition assessment
2.1. Subjects Twenty-six adults were recruited for testing. Sixteen were subjects (3 female, 13 male) with Fontan circulation from our CHD database at Royal Prince Alfred Hospital (RPAH), Sydney, Australia; nine of these subjects able to commit to an intensive 20-week isolated muscle-strengthening programme were assigned to the training arm and the other 7 were enrolled as Fontan controls. All subjects were NYHA Class I to II with resting transcutaneous oxygen saturations above 94%. Exclusion criteria included frequent symptomatic arrhythmias, clinical evidence of heart failure, symptomatic inguinal hernia, severe aortic dilatation and functionally significant physical or intellectual impairment. For the training group, major inclusion criteria were geographical proximity to the study gymnasium and work circumstances that would allow commitment to the training programme. Patient characteristics are shown in Table 1. Ten healthy age–sex matched controls were recruited from the general community for aspects of testing where healthy control data were required. Both Fontan subjects and healthy controls were required to be doing less than 2 regular exercise sessions per week to be eligible for the study. Standard magnetic resonance imaging (MRI) exclusion criteria were applied when appropriate. Informed written consent was obtained from all subjects and the study was approved by the Sydney Local Health District Ethics Review Committee (RPAH Zone). The study protocol conformed with the ethical guidelines of the Declaration of Helsinki. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [13]. 2.2. Study design Study design is illustrated in Fig. 1. Initial testing comprised cardiopulmonary exercise testing (CPET), body composition scanning via dual-energy X-ray absorptiometry (DXA) and standard cardiac MRI. In addition, calf muscle phosphorus spectroscopy (MRS) to assess skeletal muscle metabolism and real-time free breathing MR analysis (FBMR) were performed in 6 Fontan subjects, together with age and sex matched normal controls. During FBMR subjects were studied at rest, during low and moderate levels of exercise, whilst on CPAP and during a Valsalva manoeuvre. The 9 training subjects then commenced a progressive 20-week resistance-training programme. Fontan-control subjects were simply asked to continue with their usual lifestyle. At the conclusion of the 20 weeks, subjects were restudied with CPET and DXA. MRS and FBMR were repeated in 4 of the training subjects who completed the study and had initially undergone those investigations. Early into training, we learnt that, due to a technical issue, the FBMR data at baseline pre-strength training were unable to be analysed adequately. As a result, a 12-month
Total body composition and non-dominant calf composition were assessed by total body DXA (Lunar Prodigy: GE Healthcare, Milwaukee, USA) to determine lean mass and fat mass. For the calf, total body scans were analysed offline; a region of interest was placed over the calf area using the tibial plateau and the tip of the lateral malleous as landmarks. All DXA studies and offline assessment were performed by a single observer. 2.5. Phosphorus magnetic resonance spectroscopy Phosphorus magnetic resonance spectroscopy was used to non-invasively assess skeletal muscle metabolism at rest, during exercise and recovery. The scanning sequence is described in more detail within Online Supplementary Methods. Spectra were quantified using the Java-based magnetic resonance user interface (jMRUI version 2.0, EU Project) to obtain relative concentrations of inorganic phosphate, phosphocreatine (PCr) and ATP. Kinetics of post exercise PCr recovery was assessed by least-squares fit of PCr relative signal intensity time course to an exponential function. Because pH changes during exercise were minimal, the exponential rate constant of PCr recovery, k, can be taken as a measure of overall muscle mitochondrial capacity, an integrated system property depending on intrinsic mitochondrial numbers and function and on cardiovascular delivery of substrate and oxygen to the muscle. 2.6. Cardiac magnetic resonance imaging MR imaging was performed using a 1.5 T MR scanner (Philips Medical Systems, Best, The Netherlands) equipped with a 5-ch cardiac receive coil and a dedicated MR workstation (Philips Medical Systems). Detailed methodology for assessment of ventricular volumes and function together with flow quantification is included in the Supplementary Online Material. 2.7. Free breathing real-time magnetic resonance imaging Prior to entering the magnet subjects were taught to perform a Valsalva manoeuvre through instruction and demonstration and trialled on CPAP (method outlined in Supplementary Material along with detailed explanation of FBMR scanning methodology). Real-time flow measurements [2] were performed in the sequence of SVC, aorta then IVC at rest, during a Valsalva manoeuvre, after 2 min of CPAP and then during exercise. Each set of data consisted of 200 consecutive, real-time (no ECG-triggering), phase-contrast, 43 ms flow acquisitions. This equated to 8.6 s of flow data. ECG and respiratory waveforms were simultaneously collected and saved for off-line analysis.
Table 1 Patient characteristics. Trainers (n = 6) Age (years) Sex Type of repair
31 +/− 4 1 female, 5 male 2 APC, 3 intracardiac TCPC (1 with fenestration), 1 extra-cardiac conduit (converted from APC) NYHA class 3 NYHA I, 3 NYHA II Sats (%) 97 +/− 1 Age at first surgery (years) 11 +/− 4 Time since last Fontan repair (years) 21 +/− 1 Ventricular function at echocardiography 3 normal, 2 mild impairment, 1 mild–moderate impairment 2 27 +/− 1 Body mass index (kg/m )
Non-trainers (n = 5) 32 +/− 1 1 female, 4 male 2 APC, 2 intracardiac TCPC, 1 extra-cardiac conduit 3 NYHA I, 2 NYHA II 99 +/− 1 12 +/− 2 18 +/− 2 2 normal, 2 mild impairment, 1 mild–moderate impairment 25 +/− 1
Data are mean +/−SEM. Abbreviations: APC—atriopulmonary connection and TCPC—total cavopulmonary connection.
Please cite this article as: Cordina RL, et al, Resistance training improves cardiac output, exercise capacity and tolerance to positive airway pressure in Fontan physiology, Int J Cardiol (2012), http://dx.doi.org/10.1016/j.ijcard.2012.10.012
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Fig. 1. Study design. Abbreviations: CPET—cardiopulmonary exercise testing, DXA—dual X-ray absorptiometry, FBMR—free breathing magnetic resonance imaging, MRI—magnetic resonance imaging and MRS—magnetic resonance spectrometry.
The exercise protocol consisted of low (0.5 Watts/kg) and moderate (0.75 Watts/kg) levels of exercise. We did not include higher intensity exercise in the protocol as excessive movement degraded the quality of the data. Subjects exercised for 3 min before data acquisition commenced to ensure they had reached steady state and continued to exercise during scanning. There was a 3-min rest period between exercise cycles. Subjects that had repeat testing pedalled at the same cadence (regulated through verbal prompting from the study supervisor) and workload for subsequent tests. 2.7.1. MRI data calculations ECG and respiratory data were combined with relevant flow data offline. Respiratory rate and heart rate were calculated for each data set. Mean flow values were calculated over 2 breaths unless due to low respiratory rate a full data set could not be obtained over the 8.6 s scanning time, in which case just one breath was used. Inspiration was taken from the point of upstroke on the respiratory curve and expiration from the point of decline. For caval flow mean, inspiratory and expiratory blood flows were calculated. Where dual SVCs were present (n=2) total SVC flow was used. Aortic data was used to calculate mean flow and mean stroke volume, peak-expiratory flow, peak-expiratory stroke volume, trough-inspiratory flow and trough-expiratory stroke volume. Calculations account for regurgitant flow or volume and report net forward flow or stroke volume. Flow data were obtained during phase 2 of the Valsalva manoeuvre when flow was at its lowest; these values were calculated over 3 heart beats. From aortic flows the respiratory-dependent component of stroke volume was calculated as follows:
ðpeak expiratory stroke volume−trough inspiratory stroke volumeÞ: For venous flow we also calculated a respiratory dependent fraction using flow and volume calculations. The difference between inspiratory and expiratory flows was considered to represent the portion of flow that depended upon respiration [12].
The respiratory-dependent flow factor was calculated as follows: ðinspiratory flow−expiratory flowÞ=mean flow: Inspiratory and expiratory volumes were treated similarly with the respiratorydependent blood volume factor calculated using the equation: ðinspiratory volume−expiratory volumeÞ=total volume where blood volumes were calculated from the area under the flow curve occurring during the cardiac or relevant phase of respiratory cycle. One subject's SVC data was excluded from analysis as he had a small arteriovenous shunt close to the pulmonary anastmosis, seen at cardiac MRI. Combined resting SVC and IVC flow differed 6.6% from mean aortic flow similar to previously reported values [2]. The difference between exercise measurements was 13.1%. 2.8. Strength training Training subjects underwent a regimen of high-intensity total body resistance training with a focus on calf muscle strengthening, 3 days per week for 20 weeks after baseline strength testing. Exercises included the chest press, lat (latissimus dorsi) pull-down alternating each session with seated row, leg press, knee extension, knee flexion, hack calf and seated calf (Keiser Sports Health Equipment, California, USA). Strength testing and training techniques are described in detail in Supplementary Material. Subjects were trained in weight-lifting technique; straining with a Valsalva during a lift was discouraged and they were taught to exhale through the strain to avoid a marked reduction in cardiac output. Participants performed 3 sets of 8 repetitions on each machine. Each session lasted approximately 60 min. All sessions were carefully supervised with one trainer per 3 subjects at most.
Please cite this article as: Cordina RL, et al, Resistance training improves cardiac output, exercise capacity and tolerance to positive airway pressure in Fontan physiology, Int J Cardiol (2012), http://dx.doi.org/10.1016/j.ijcard.2012.10.012
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There were 3 drop-outs from the training group. One training subject decided the commitment to training was too great after attending 3 training sessions and withdrew from the study, another suffered a transient ischemic episode over a weekend, 3 days after his most recent training session. He commenced anticoagulation and suffered from substantial nose-bleeds as a result before training had resumed. Although the risk of bleeding related to strain during weight lifting was considered small he was withdrawn from the study. The final drop-out occurred towards the end of training. He moved to a rural area and was unable to continue attending the gymnasium sessions as a result. Two non-training Fontan subjects did not return for follow-up testing. 2.9. Statistical analysis The prespecified primary study end-point was change in peak VO2 after strength training. Other parameters were not adjusted for multiple comparisons as they were exploratory variables to understand mechanisms of any observed change in exercise performance such as stroke volume, cardiac output and respiratory dependence. All variables are expressed as mean +/− SEM. Within subject comparisons were analysed by paired Student's t tests. For between group analysis unpaired Student's t tests were employed. SPSS statistics Data Editor (IBM Corporation, New York, USA) was used for statistical calculations. A two-tailed p-value ≤0.05 was considered statistically significant.
3. Results 3.1. Study group characteristics Subject characteristics are summarised in Table 1. The 4 male and 2 female Fontan subjects who underwent MRS testing, were aged 32+/−4 years and for sex-matched controls age was 33+/− 3 years (p=NS). For free breathing MRI, mean age of the all-male Fontan subgroup was 29+/−5 years, body surface area (BSA) was 2.05+/− 0.07 m2 in the trained state and 2.02+/−0.09 m2 in the detrained state, total body lean mass percentage was 67+/−1% in the trained state and 65+/−1% in the detrained state. In comparison, for the sex-matched controls age was 34+/−5 years, BSA was 1.90+/− 0.07 m2 and total lean mass was 67+/−0% (p=NS for all). Mean time to follow-up was 21+/−1 weeks in the training group and 19+/−1 weeks in the non-trainers. The detraining period was 56+/− 2 weeks. No alterations in pharmacotherapy occurred for any Fontan subject during the study. Anatomical characteristics are described in Table 2. 3.2. Cardiac magnetic resonance imaging
4.0% and atrioventricular valve regurgitant fraction was 5+/−2% (detailed flow data is not shown). 3.3. Strength training For the 6 subjects completing the 20-week training programme 43 +/− 3 training sessions were attended per subject and gym attendance was 76 +/− 5%. Strength increased by 43 +/− 7% (p = 0.002) with training. There were no cardiac arrhythmia events observed during the programme or other reported cardiac events apart from the subject described in Section 2.8. 3.4. Body composition scanning Results of trainers compared with non-trainers are shown in Fig. 2a (1.94+/− 0.52 vs. −0.80 +/− 0.36 kg, p = 0.003 for total body lean mass and 101 +/− 15 vs. −19+/− 26 g, p =0.002 for non-dominant calf lean mass, n= 11 for both). Following the 12-month detraining period total body lean mass fell from 56.3+/− 2.7 kg to 53.1+/− 2.5 kg (n=4, p = 0.03) and calf lean mass fell from 2353 +/− 183 g to 2254+/− 197 g (n= 4, p =0.03). Overall body weight fell after detraining (84.8 +/− 5.6 vs. 82.6 +/− 5.1 kg, p = 0.05). 3.5. Cardiopulmonary exercise testing At baseline, peak VO2 was 71+/−6% of predicted normal values in the training group and 60+/−19% in the non-trainers (p=NS). Training was associated with a significant increase in peak VO2 (see Fig. 2b; Δ183+/−31 vs. 5+/−39 ml/min, p=0.02 equivalent to Δ9.5+/−2.4 vs. 1.4+/−2.9% from baseline, p=0.03, n=10 for both). In terms of percent predicted values, trainers' VO2 increased by 7+/−2% compared with 1+/−1% in non-trainers (p=0.01, n=10). Other peak exercise parameters were altered but not significantly so; Δ workload 9.8+/−4.7 vs. −0.2+/−3.5 Watts, p=0.128, Δ heart rate −2+/−3 vs. 2+/− 2 bpm, p=0.368, Δ carbon dioxide output (VCO2) 141+/−83 vs. −33+/−82 ml/min, p=0.172, Δ minute ventilation (Ve) 8.0+/−4.9 vs. 2.5+/−3.4 l/min, p=0.388, Δ respiratory quotient −0.03+/−0.04
Five subjects from the training group underwent testing at baseline. Stroke volume was 97.2+/−7.2 ml, ejection fraction was 51.8+/− 2.6%, cardiac output was 7.5+/−0.8 l/min, aortic valve regurgitant fraction was 11.7+/−3.5% and atrioventicular valve regurgitant fraction was 11.0+/−4.6%. Of the non-trainers only 2 had testing; stroke volume was 90.5+/−15.5 ml, ejection fraction was 44.0+/−5.0%, cardiac output was 6.2+/−0.5 l/min, aortic valve regurgitant fraction was 16.0+/− Table 2 Anatomical characteristics. Training subjects 1. 2. 3. 4. 5. 6.
Tricuspid atresia Dextrocardia, tricuspid atresia, VSD, subpulmonary stenosis and TGA DILV, hypoplastic tricuspid valve and subpulmonary stenosis Dual-SVC, mitral atresia, VSD and TGA HLHS, VSD, subpulmonary stenosis and TGA Dual-SVC, VSD, DORV, pulmonary stenosis
Non-training subjects 1. 2. 3. 4. 5.
Tricuspid atresia, subpulmonary stenosis and TGA Hypoplastic right ventricle, tricuspid valve and pulmonary valve, VSD and TGA Dextrocardia, DILV, pulmonary atresia DORV Dextrocardia, right AV-valve atresia, cc-TGA, DORV and pulmonary stenosis
Abbreviations: AV—atrioventricular, cc-TGA—congenitally corrected transposition of the great arteries, DILV—double inlet left ventricle, DORV—double outlet right ventricle, HLHS—hypoplastic left heart syndrome, SVC—superior vena cava, TGA—transposition of the great arteries, and VSD—ventricular septal defect.
Fig. 2. Change in lean mass and peak VO2 with resistance training versus non-training controls. Error bars shown are SEM. Abbreviations: VO2 oxygen uptake.
Please cite this article as: Cordina RL, et al, Resistance training improves cardiac output, exercise capacity and tolerance to positive airway pressure in Fontan physiology, Int J Cardiol (2012), http://dx.doi.org/10.1016/j.ijcard.2012.10.012
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vs. −0.04+/−0.03, p=0.726, Δ oxygen pulse 1.2+/−0.7 vs. −0.02+/−0.2 ml/beat, p=0.133, Δ anaerobic threshold 21+/−9 vs. 3+/−8 Watts, p=0.15. There was no significant difference between trainers and non-trainers when CPET data were analysed at 0.8 isotime (detailed data not shown).
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The results observed following the 12-month detraining period are shown in Fig. 3a–b (peak VO2: 2.4+/−0.2 vs. 1.9+/−0.2 l/min, pb 0.001, peak VCO2: 2.7+/−0.2 vs. 2.2+/−0.2, pb 0.001, peak Ve: 102.6+/−17.7 vs. 79.1+/−15.6 l/min, p=0.01, oxygen pulse: 14.7+/−1.0 vs. 12.3+/−0.7 ml/beat, p=0.005, anaerobic threshold
Fig. 3. Trained state versus detrained state at exercise testing and during free-breathing magnetic resonance imaging. a and b: Cardiopulmonary exercise testing parameters; c: stroke volume; d: mean aortic flow; e: mean inferior vena caval flow; f: expiratory inferior vena caval flow; g: respiratory-dependence factor for inferior vena caval blood return. Error bars shown are SEM. Abbreviations: CPAP—constant positive airway pressure, IVC–inferior vena cava, VCO2—carbon dioxide production, Ve—minute ventilation, VO 2 oxygen uptake and W—Watts.
Please cite this article as: Cordina RL, et al, Resistance training improves cardiac output, exercise capacity and tolerance to positive airway pressure in Fontan physiology, Int J Cardiol (2012), http://dx.doi.org/10.1016/j.ijcard.2012.10.012
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Fig. 3 (continued).
144+/−12 vs. 118+/−15 Watts, p=0.05, peak workload: 173+/−15 vs. 149+/−19 Watts, p=0.01, n=4 for all). In terms of percent predicted values peak VO2 fell from 73+/−4 to 59+/−8% (pb 0.001, n=4). At 0.8 isotime, VCO2 was lower in the trained state at that workload (1.54+/−0.09 vs. 1.69+/−0.07 l/min, p=0.05, n=4).
3.7. Free breathing real-time magnetic resonance imaging
3.6. Phosphorus magnetic resonance spectroscopy
3.7.1. The Fontan circulation in the trained and untrained states versus normal controls Fontan subjects, in both the trained and detrained states, rely more heavily on inspiration for cardiac filling than normal controls; at rest, the respiratory dependent component of stroke volume was significantly greater in Fontan subjects (20.3+/− 2.5 vs. 5.5+/− 2.0 ml, p =0.004
Baseline MRS assessment suggested an impaired PCr recovery constant compared with normal controls (1.58+/−0.16 vs. 2.15+/− 0.20, p=0.06, n =6). Muscle aerobic capacity tended to improve with training (1.34+/− 0.13 vs. 1.63+/−0.14, p=0.09, n =4).
Adjustment of results for BSA did not alter statistical significance; results are reported as absolute measurements. Heart rates and respiratory rates recorded during testing are included in online Supplementary Material (Table A).
Please cite this article as: Cordina RL, et al, Resistance training improves cardiac output, exercise capacity and tolerance to positive airway pressure in Fontan physiology, Int J Cardiol (2012), http://dx.doi.org/10.1016/j.ijcard.2012.10.012
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lower in the detrained state (24.7+/− 10.4 vs. −1.2 +/− 5.0%, p= 0.07, n= 8) but not in the trained state (17.6+/− 15.0 vs. −1.2 +/− 5.0%, p =0.278, n= 8). During exercise, the increase in aortic flow from baseline at moderate levels of exertion was lower in Fontan subjects (44.3+/− 11.2 vs. 78.2+/− 10.8 ml/s, p = 0.07 in the trained state, 42.1+/− 5.8 vs. 78.2 +/− 10.8 ml/s, p = 0.03 in the detrained state). In keeping with aortic analysis, increased respiratory dependence was also observed in the IVC associated with reduced expiratory flows both at rest and exercise in both the trained and detrained states (see Table 3). In the SVC differences in flow between Fontan and normal subjects were only detectable during exercise (at 0.75 Watts/kg expiratory flow was less in Fontan subjects; 19.2+/− 3.3 vs. 37.2 +/− 3.7 ml/s trained state, 18.7 +/− 1.6 vs. 37.2+/− 3.7 ml/s detrained state, p = 0.01, n =7 for both). 3.7.2. The Fontan circulation in the trained versus detrained state Results are demonstrated in Fig. 3c–g. Stroke volume increased at rest (77.8 +/− 10.3 vs. 66.7 +/− 9.3 ml, p =0.01, n = 4) and during exercise (86.5+/− 10.7 vs. 72.2 +/− 7.8 ml at 0.5 Watts/kg, p =0.06 and 90.9 +/− 11.9 vs. 75.0+/− 10.2 ml at 0.75 Watts/kg, p =0.04, n=4 for both). Mean aortic flow was higher at rest and on CPAP (100 +/− 10 vs. 83 +/−10 ml/s, 101 +/− 17 vs. 77 +/−12 ml/s respectively, p = 0.03, n= 4 for both) and tended to be higher at low intensity exercise (130 +/− 18 vs. 108 +/− 11 ml/s, p= 0.06, n=4). Mean flow in the IVC was lower at rest (65 +/−8 vs. 53 +/−8 ml/s, p =0.007, n=4) with augmented expiratory IVC flow both at rest and during exercise (34 +/− 11 vs. 16 +/− 8 ml/s at rest, p = 0.04, 43 +/− 10 vs. 22+/− 6 ml/s at 0.5 Watts/kg, p = 0.02, 42 +/− 13 vs. 16 +/− 19 ml/s at 0.75 Watts/kg, p = 0.09, n = 4 for all). At rest there was no difference in the respiratory-dependent fraction of IVC blood return between the trained and detrained states (0.46 +/− 0.15 vs. 0.72 +/− 0.15, p = 0.16, n = 4) however there was a significant difference observed during exercise (Fig. 3g; 0.58+/−0.09 vs. 0.81+/−0.02 at0.5 Watts/kg, p=0.02, 0.62+/−0.08 vs. 0.88+/−0.16 at 0.75 Watts/kg, p=0.08, 0.60+/−0.16 vs. 0.84+/−0.21 for mean exercise, p=0.004, n =4 for all). The respiratory-dependent flow factor also improved in the trained
Table 3 Expiratory IVC flow and respiratory dependence in trained and detrained Fontan subjects versus normal controls.
Rest
Expiratory flow (ml/s)
Respiratory dependent volume factor CPAP
Expiratory flow (ml/s)
Respiratory dependent volume factor 0.5 Watts/kg
Fig. 3 (continued).
in the trained state; 20.1+/− 3.9 vs. 5.5 +/− 2.0 ml, p= 0.02 in the detrained state, n =8). On CPAP the peak expiratory stroke volume (compared with peak rest values) tended to fall more in the detrained state (8.4 +/−2.6 vs. 0.8+/− 2.3%, p =0.07, n = 8); this tendency was not observed in the trained state (1.2 +/−5.9 vs. 0.8 +/− 2.3%, p =0.946, n = 8). Furthermore during a Valsalva manoeuvre, stroke volume also tended to be
Expiratory flow (ml/s)
Respiratory dependent volume factor 0.75 Watts/kg
Expiratory flow (ml/s)
Respiratory dependent volume factor
Trained state
Detrained state
33.6 +/−10.5 vs. 53.4 +/−4.3 p = 0.14 0.46 +/−0.15 vs. 0.03 +/−0.15 p = 0.09 18.9 +/− 9.3 vs. 53.2 +/− 9.0 p = 0.04 0.73 +/− 0.13 vs. 0.26 +/− 0.19 p = 0.08 42.6 +/− 10.2 vs. 93.8 +/− 9.3 p = 0.01 0.58 +/− 0.09 vs. 0.08 +/− 0.08 p = 0.006 42.4 +/− 12.9 vs. 110.5 +/−4.6 p = 0.008 0.62 +/− 0.08 vs. 0.07 +/− 0.11 p = 0.01
16.0 +/− 7.8 vs. 53.4 +/− 4.3 p = 0.006 0.72 +/− 0.15 vs. 0.03 +/− 0.15 p = 0.02 15.6 +/− 7.4 vs. 53.2 +/− 9.0 p = 0.02 0.88 +/− 0.05 vs. 0.26 +/− 0.19 p = 0.02 22.1 +/− 6.2 vs. 93.8 +/− 9.3 p = 0.001 0.81 +/− 0.06 vs. 0.08 +/− 0.08 p b 0.001 15.5 +/− 18.7 vs. 110.5 +/− 4.6 p = 0.008 0.88 +/− 0.16 vs. 0.07 +/− 0.11 p = 0.01
Abbreviations: CPAP—constant positive airway pressure, and IVC—inferior vena cava. Significant results (p b 0.05) are shown in bold text.
Please cite this article as: Cordina RL, et al, Resistance training improves cardiac output, exercise capacity and tolerance to positive airway pressure in Fontan physiology, Int J Cardiol (2012), http://dx.doi.org/10.1016/j.ijcard.2012.10.012
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state compared with the detrained state (0.53 +/−0.07 vs. 0.76 +/− 0.08, p =0.009 at rest, 0.49+/− 0.08 vs. 0.69+/− 0.06, p =0.004 at 0.5 Watts/kg, 0.58 +/− 0.07 vs. 0.81 +/− 0.23, p = 0.269 at 0.75 Watts/kg, n = 4 for all). By contrast, analysis of data obtained from the SVC did not reveal any differences between the trained and detrained states.
4. Discussion In this study of exercise pathophysiology in the setting of the Fontan circulation, we have found that isolated muscle resistance training (without additional aerobic training) significantly increases exercise capacity. In exploring potential mechanisms, we found that augmenting peripheral muscle is associated with improvements in cardiac filling and cardiac output at rest, exercise and during inspiratory stress as well as reduced dependence on respiration for blood to return to the heart via the IVC. We postulate that these physical changes are due to increased muscle bulk and improvement of the peripheral muscle pump. In the normal circulation, higher peripheral muscle bulk reduces venous compliance at rest and, as a result, increases preload with resulting elevations in stroke volume and cardiac output [11,14–16]. Our data suggest that the same may be true in the Fontan circulation; post-training subjects, at rest, had increased IVC flow, stroke volume and cardiac output. In addition, increased IVC flow was seen during expiration, presumably also through augmentation of peripheral muscle bulk. This resultant increase in expiratory IVC flow meant reduced respiratory dependence with improved cardiac performance during a Valsalva manoeuvre and CPAP; two situations that attenuate negative intrathoracic pressure important for cardiac filling in the Fontan circulation. Exercising muscles pump blood into the venous system. Furthermore, peripheral muscle training results in increased vascularization of targeted muscle-groups [17] leading to greater “stroke volume” from exercising muscles with each movement [18,19]. This, in addition to the effects described at rest, may be another contributor to the improved cardiac output and stroke volume during exercise observed post-training in our study. Oxygen pulse data obtained from CPET in our subjects support the concept that improved cardiac stroke volume in the trained state contributed to better exercise performance. Traditionally, intensive strength training has been discouraged in cardiac disease although it has emerged as an important component of cardiac rehabilitation [20]. Straining during weight training is potentially associated with marked elevations in blood pressure [21] and subjects with a Fontan circulation are particularly susceptible to falls in cardiac output during a Valsalva manoeuvre, commonly performed during heavy weightlifting. We educated our training subjects appropriately and did not encounter any significant cardiovascular events during the programme; training sessions were carefully supervised. To our knowledge, isolated strength training to enhance exercise performance in subjects palliated with a Fontan procedure has not previously been investigated and a documented improvement in exercise performance through any type of training programme (that has included a control group for comparison) has not been reported. Brassard et al. [22,23] described the effects of a combined aerobic and light-resistance training programme in Fontan subjects compared with a control-Fontan group. They did not observe a significant improvement in peak VO2 following the 8-week regimen however an improvement in skeletal muscle ergoreceptor function was reported. We also observed alterations in muscle function; a shift in anaerobic threshold and MRS results suggested improved skeletal muscle aerobic function with training, another novel finding from this current report. A small number of other studies have shown improvements in exercise performance and oxygen pulse through aerobic training with uncontrolled study design in largely paediatric populations that have included some young adults [23–25]. It is well-recognised that improved strength is associated with higher levels of performance in health and disease [22,26] but our findings suggest
that, in the Fontan group, gains in strength are also associated with improved cardiac filling and output. In elegant studies, Hjortdal et al. [2] demonstrated the respiratory dependence of the Fontan circulation, using free breathing MRI. They also described an attenuation of respiratory dependence during lower limb exercise, suggesting that a peripheral pump could contribute to some of the work usually done by the respiratory bellows. Our findings extend these short-term findings and demonstrate that augmentation of peripheral muscle bulk may reduce the respiratory dependence for cardiac filling. In addition, a reduction in respiratory dependence likely reduces the work of breathing. Direct measurement of breathing work is invasive and therefore we did not include it in our study protocol but studies have shown that increased work of breathing leads to compromised locomotor blood flow and cardiac function both in health and heart failure [27]. This may be an additional mechanism whereby strength training could be beneficial for Fontan subjects. It is widely known that subjects with the Fontan circulation tolerate positive pressure ventilation poorly, as attenuation of negative intrathoracic pressure decreases cardiac filling [28]. For the first time we have demonstrated that augmentation of the peripheral muscle pump is associated with improved cardiac output during CPAP, which is of potential clinical significance considering the risk of reduced cardiac output during general anaesthesia, in Fontan subjects [3,29]. Limitations of our study include the lack of baseline FBMR data due to technical difficulties initially encountered. Nevertheless, we have information from two distinct untrained states; baseline and 12 months post-training cessation. Whilst the detraining period became necessary due to these technical issues, the additional information obtained enhances confidence that the changes seen post-training were indeed due to the training related increase in peripheral muscle mass. Our study was also limited by small numbers; this was in part, due to the time commitment required for the training programme and the need to live in close proximity to the training facility. In conclusion, our research suggests that strength training is safe and may have important benefits for cardiac function and exercise performance in subjects with the Fontan-type circulation. Strength training to augment peripheral muscle bulk may be an important component of routine management in this group and warrants further investigation.
Conflict of interest Carsten Liess is employed as a clinical scientist with Philips Healthcare. We did not acquire external funding for this project. All authors approve submission.
Acknowledgements The authors wish to thank their enthusiastic study participants, Mr Rowley Hilder for constructing the MRI ergometer and output system and A/Professor David Richmond for his considerate comments on the manuscript. Dr Jennifer Alison and Mr Phillip Munoz, Royal Prince Alfred Hospital, Sydney, Australia for providing expert advice in the area of exercise physiology, Mr Nathan Malitz and Mrs Helen Lackey, Specialist Magnetic Resonance Imaging, Sydney, Australia and Mr Ken Rayner and Mr Daniel Moran, Diagnostic Medical Services, Neuroscience Research Australia, for expert radiography, the staff at the STRONG Clinic, Balmain Hospital for sharing their expertise in resistance training and Dr Craig Phillips and Mr George Dungan, Woolcock Institute, Sydney, Australia for lending expertise in non-invasive ventilation. The MRUI software package was kindly provided by the participants of the EU Network programmes: Human Capital and Mobility, [CHRX-CT94-0432] and Training and Mobility of Researchers, [ERB-FMRX-CT970160].
Please cite this article as: Cordina RL, et al, Resistance training improves cardiac output, exercise capacity and tolerance to positive airway pressure in Fontan physiology, Int J Cardiol (2012), http://dx.doi.org/10.1016/j.ijcard.2012.10.012
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Appendix A. Supplementary data Supplementary data to this article can be found online at http:// dx.doi.org/10.1016/j.ijcard.2012.10.012. References [1] Fontan F, Mounicot FB, Baudet E, Simonneau J, Gordo J, Gouffrant JM. “Correction” of tricuspid atresia. 2 cases “corrected” using a new surgical technic. Ann Chir Thorac Cardiovasc Jan 1971;10(1):39-47. [2] Hjortdal VE, Emmertsen K, Stenbog E, et al. Effects of exercise and respiration on blood flow in total cavopulmonary connection: a real-time magnetic resonance flow study. Circulation Sep 9 2003;108(10):1227-31. [3] Lofland GK. The enhancement of hemodynamic performance in Fontan circulation using pain free spontaneous ventilation. Eur J Cardiothorac Surg Jul 2001;20(1):114-8 [discussion 8–9]. [4] Paridon SM, Mitchell PD, 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 Jul 8 2008;52(2):99–107. [5] Driscoll DJ, Danielson GK, Puga FJ, Schaff HV, Heise CT, Staats BA. Exercise tolerance and cardiorespiratory response to exercise after the Fontan operation for tricuspid atresia or functional single ventricle. J Am Coll Cardiol May 1986;7(5):1087-94. [6] Rhodes J, Garofano RP, Bowman Jr FO, Grant GP, Bierman FZ, Gersony WM. Effect of right ventricular anatomy on the cardiopulmonary response to exercise. Implications for the Fontan procedure. Circulation Jun 1990;81(6):1811-7. [7] Shachar GB, Fuhrman BP, Wang Y, Lucas Jr RV, Lock JE. Rest and exercise hemodynamics after the Fontan procedure. Circulation Jun 1982;65(6):1043-8. [8] Guyton AC. Determination of cardiac output by equating venous return curves with cardiac response curves. Physiol Rev Jan 1955;35(1):123-9. [9] Di Bello V, Santoro G, Talarico L, et al. Left ventricular function during exercise in athletes and in sedentary men. Med Sci Sports Exerc Feb 1996;28(2):190-6. [10] Bevegard BS, Shepherd JT. Regulation of the circulation during exercise in man. Physiol Rev Apr 1967;47(2):178-213. [11] Convertino VA, Doerr DF, Flores JF, Hoffler GW, Buchanan P. Leg size and muscle functions associated with leg compliance. J Appl Physiol Mar 1988;64(3):1017-21. [12] Hsia TY, Khambadkone S, Redington AN, Migliavacca F, Deanfield JE, de Leval MR. Effects of respiration and gravity on infradiaphragmatic venous flow in normal and Fontan patients. Circulation Nov 7 2000;102(19 Suppl. 3):III148-53. [13] Coats AJ, Shewan LG. Statement on authorship and publishing ethics in the international journal of cardiology. Int J Cardiol Dec 15 2011;153(3):239-40.
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[14] Convertino VA, Doerr DF, Stein SL. Changes in size and compliance of the calf after 30 days of simulated microgravity. J Appl Physiol Mar 1989;66(3):1509-12. [15] Smith ML, Raven PB. Cardiovascular responses to lower body negative pressure in endurance and static exercise-trained men. Med Sci Sports Exerc Oct 1986;18(5):545-50. [16] Tesch PA, Hjort H, Balldin UI. Effects of strength training on G tolerance. Aviat Space Environ Med Aug 1983;54(8):691-5. [17] Anton MM, Cortez-Cooper MY, DeVan AE, Neidre DB, Cook JN, Tanaka H. Resistance training increases basal limb blood flow and vascular conductance in aging humans. J Appl Physiol Nov 2006;101(5):1351-5. [18] Sheriff DD. Muscle pump function during locomotion: mechanical coupling of stride frequency and muscle blood flow. Am J Physiol Jun 2003;284(6):H2185-91. [19] Rowland TW. The circulatory response to exercise: role of the peripheral pump. Int J Sports Med Nov 2001;22(8):558-65. [20] Williams MA, Haskell WL, Ades PA, et al. Resistance exercise in individuals with and without cardiovascular disease: 2007 update: a scientific statement from the American Heart Association Council on Clinical Cardiology and Council on Nutrition, Physical Activity, and Metabolism. Circulation Jul 31 2007;116(5):572-84. [21] de Vos NJ, Singh NA, Ross DA, Stavrinos TM, Orr R, Fiatarone Singh MA. Continuous hemodynamic response to maximal dynamic strength testing in older adults. Arch Phys Med Rehabil Feb 2008;89(2):343-50. [22] Brassard P, Poirier P, Martin J, et al. Impact of exercise training on muscle function and ergoreflex in Fontan patients: a pilot study. Int J Cardiol Feb 8 2006;107(1):85-94. [23] Rhodes J, Curran TJ, Camil L, et al. Impact of cardiac rehabilitation on the exercise function of children with serious congenital heart disease. Pediatrics Dec 2005;116(6): 1339-45. [24] Minamisawa S, Nakazawa M, Momma K, Imai Y, Satomi G. Effect of aerobic training on exercise performance in patients after the Fontan operation. Am J Cardiol Sep 15 2001;88(6):695-8. [25] Opocher F, Varnier M, Sanders SP, et al. Effects of aerobic exercise training in children after the Fontan operation. Am J Cardiol Jan 1 2005;95(1):150-2. [26] Hamilton AL, Killian KJ, Summers E, Jones NL. Muscle strength, symptom intensity, and exercise capacity in patients with cardiorespiratory disorders. Am J Respir Crit Care Med Dec 1995;152(6 Pt 1):2021-31. [27] Miller JD, Smith CA, Hemauer SJ, Dempsey JA. The effects of inspiratory intrathoracic pressure production on the cardiovascular response to submaximal exercise in health and chronic heart failure. Am J Physiol Jan 2007;292(1):H580-92. [28] Watson NF, Bushnell T, Jones TK, Stout K. A novel method for the evaluation and treatment of obstructive sleep apnea in four adults with complex congenital heart disease and Fontan repairs. Sleep Breath Nov 2009;13(4):421-4. [29] Penny DJ, Hayek Z, Redington AN. The effects of positive and negative extrathoracic pressure ventilation on pulmonary blood flow after the total cavopulmonary shunt procedure. Int J Cardiol Jan 1991;30(1):128-30.
Please cite this article as: Cordina RL, et al, Resistance training improves cardiac output, exercise capacity and tolerance to positive airway pressure in Fontan physiology, Int J Cardiol (2012), http://dx.doi.org/10.1016/j.ijcard.2012.10.012
Contents lists available at SciVerse ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Resistance training improves cardiac output, exercise capacity and tolerance to positive airway pressure in Fontan physiology☆ Rachael L. Cordina a, b, Shamus O'Meagher a, b, Alia Karmali a, Caroline L. Rae c, d, Carsten Liess e, Graham J. Kemp f, Raj Puranik a, b, Nalin Singh g, h, David S. Celermajer a, b,⁎ a
Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia Department of Cardiology, Sydney Medical School, Sydney, Australia Neuroscience Research Australia, Sydney, Australia d Faculty of Medicine, University of New South Wales, Sydney, Australia e Philips Healthcare, Sydney, Australia f Departments of Musculoskeletal Biology and Magnetic Resonance and Image Analysis Research Centre, University of Liverpool, Liverpool, United Kingdom g Department of Aged Care, Royal Prince Alfred Hospital, Sydney, Australia h Department of Aged Care, Balmain Hospital, Sydney, Australia b c
a r t i c l e
i n f o
Article history: Received 9 August 2012 Accepted 7 October 2012 Available online xxxx Keywords: Congenital heart disease Single ventricle Fontan operation Cardiac rehabilitation Exercise training Cardiac function
a b s t r a c t Background: Subjects with Fontan-type circulation have no sub-pulmonary ventricle and thus depend exquisitely on the respiratory bellows and peripheral muscle pump for cardiac filling. We hypothesised that resistance training to augment the peripheral muscle pump might improve cardiac filling, reduce inspiratory-dependence of IVC return to the heart and thus improve exercise capacity and cardiac output on constant positive airway pressure (CPAP). Methods: Eleven Fontan subjects (32+/− 2 years, mean+/−SEM) had cardiac magnetic resonance imaging (MRI) and exercise testing (CPET); six underwent 20 weeks of high-intensity resistance training; others were non-exercising controls. After training, CPET was repeated. Four trainers had MRI with real-time flow measurement at rest, exercise and on CPAP in the trained state and following a 12-month detrain. Results: In the trained state, muscle strength increased by 43% (p =0.002), as did total muscle mass (by 1.94 kg, p=0.003) and peak VO2 (by 183 ml/min, p=0.02). After detraining, calf muscle mass and peak workload had fallen significantly (p b 0.03 for both) as did peak VO2 (2.72 vs. 2.18 l/min, pb 0.001) and oxygen pulse, a surrogate for SV (16% lower, p=0.005). Furthermore after detraining, SV on MRI decreased at rest (by 11 ml, p =0.01) and during moderate-intensity exercise (by 16 ml, p=0.04); inspiratory-dependent IVC blood return during exercise was 40% higher (p=0.02). On CPAP, cardiac output was lower in the detrained state (101 vs. 77 ml/s, p=0.03). Conclusions: Resistance muscle training improves muscle mass, strength and is associated with improved cardiac filling, stroke volume, exercise capacity and cardiac output on CPAP, in adults with Fontan-type circulation. Crown Copyright © 2012 Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction First described in 1971 by Fontan and Kreutzer [1] as a surgical option for patients with tricuspid atresia, the remarkable Fontan procedure is now commonly performed to palliate various forms of essentially single-ventricle congenital heart disease (CHD), with increasing numbers surviving to adulthood. The Fontan circuit, which functions without the sub-pulmonary ventricle as a power source to pump blood through the
☆ All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ⁎ Corresponding author at: Department of Cardiology, Royal Prince Alfred Hospital, Missenden Rd, Camperdown, NSW 2050, Australia. Tel.: +61 2 9515 6111; fax: +61 2 9550 6262. E-mail address: [email protected] (D.S. Celermajer).
lungs, relies heavily on the respiratory bellows to draw blood into the pulmonary vascular bed during inspiration [2]. As a consequence, cardiac output in these subjects falls during positive pressure ventilation [3]. Despite surgical advances in the Fontan operation there are important long-term consequences from living without a sub-pulmonary circulatory pump. Whilst subjects with a well-functioning Fontan-type circulation perform quite well during low-level day-to-day activities, they are generally limited during more intense levels of exercise; a major contributor to this limitation is reduced cardiac filling, due to the altered anatomy and physiology [4–7]. Even the normal heart cannot increase cardiac output more than a few percent without the aid of the periphery [8]. During upright exercise the peripheral pumping mechanism must overcome the effects of gravity to enable diastolic filling. At the onset of exercise stroke volume rises, by about the same volume as when a subject goes from supine to sitting [9]. This refilling of the ventricle is from blood mobilised from the
0167-5273/$ – see front matter. Crown Copyright © 2012 Published by Elsevier Ireland Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ijcard.2012.10.012
Please cite this article as: Cordina RL, et al, Resistance training improves cardiac output, exercise capacity and tolerance to positive airway pressure in Fontan physiology, Int J Cardiol (2012), http://dx.doi.org/10.1016/j.ijcard.2012.10.012
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lower extremities [10]. In addition, venous compliance in the leg has been shown in normal subjects to have a close negative correlation with calf surface area and muscle mass [11] and in the Fontan circulation the effects of gravity have been shown to adversely affect anterograde inferior vena caval (IVC) flow [12]. This suggests that an enhanced peripheral muscle mass and associated skeletal muscle pump could be especially important in those with Fontan physiology. We hypothesised that muscle resistance training to augment the peripheral muscle pump might improve cardiac filling and stroke volume in the Fontan circulation and reduce the inspiratory dependence of IVC blood return to the heart. For the same reasons, we postulated that resistance training might also improve exercise capacity and cardiac output during constant positive airway pressure (CPAP).
detrain period was added to the project for these 4 FBMR subjects, so that they could be analysed in both trained and detrained states. 2.3. Cardiopulmonary exercise testing CPET comprised a ramp-protocol cycle test on an electrically braked bicycle ergometer (Lode Corival; Lode BV, Groningen, The Netherlands). CPET method is described in detail elsewhere (see Online Supplement). Oxygen pulse, a surrogate for stroke volume during CPET, was calculated by dividing VO2 (oxygen uptake) by heart rate. Anaerobic threshold was calculated using the V-slope method, by a blinded observer [13]. Peak VO2 and peak workload were compared to predicted normal values [14]. Eighty percent of the untrained peak work (0.8 isotime) was calculated and important parameters were then compared at that workload. Delta values were calculated by subtracting the post-training (or in the case of non-trainers, post-control period) result from the baseline result. One training subject stopped his post-training CPET prematurely due to anxiety. At the point of cessation his physiologic parameters (such as heart rate, respiratory quotient and VO2) suggested he had not reached exhaustion and thus this subject's data were subsequently removed, from peak exercise data analysis only.
2. Methods 2.4. Body composition assessment
2.1. Subjects Twenty-six adults were recruited for testing. Sixteen were subjects (3 female, 13 male) with Fontan circulation from our CHD database at Royal Prince Alfred Hospital (RPAH), Sydney, Australia; nine of these subjects able to commit to an intensive 20-week isolated muscle-strengthening programme were assigned to the training arm and the other 7 were enrolled as Fontan controls. All subjects were NYHA Class I to II with resting transcutaneous oxygen saturations above 94%. Exclusion criteria included frequent symptomatic arrhythmias, clinical evidence of heart failure, symptomatic inguinal hernia, severe aortic dilatation and functionally significant physical or intellectual impairment. For the training group, major inclusion criteria were geographical proximity to the study gymnasium and work circumstances that would allow commitment to the training programme. Patient characteristics are shown in Table 1. Ten healthy age–sex matched controls were recruited from the general community for aspects of testing where healthy control data were required. Both Fontan subjects and healthy controls were required to be doing less than 2 regular exercise sessions per week to be eligible for the study. Standard magnetic resonance imaging (MRI) exclusion criteria were applied when appropriate. Informed written consent was obtained from all subjects and the study was approved by the Sydney Local Health District Ethics Review Committee (RPAH Zone). The study protocol conformed with the ethical guidelines of the Declaration of Helsinki. The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology [13]. 2.2. Study design Study design is illustrated in Fig. 1. Initial testing comprised cardiopulmonary exercise testing (CPET), body composition scanning via dual-energy X-ray absorptiometry (DXA) and standard cardiac MRI. In addition, calf muscle phosphorus spectroscopy (MRS) to assess skeletal muscle metabolism and real-time free breathing MR analysis (FBMR) were performed in 6 Fontan subjects, together with age and sex matched normal controls. During FBMR subjects were studied at rest, during low and moderate levels of exercise, whilst on CPAP and during a Valsalva manoeuvre. The 9 training subjects then commenced a progressive 20-week resistance-training programme. Fontan-control subjects were simply asked to continue with their usual lifestyle. At the conclusion of the 20 weeks, subjects were restudied with CPET and DXA. MRS and FBMR were repeated in 4 of the training subjects who completed the study and had initially undergone those investigations. Early into training, we learnt that, due to a technical issue, the FBMR data at baseline pre-strength training were unable to be analysed adequately. As a result, a 12-month
Total body composition and non-dominant calf composition were assessed by total body DXA (Lunar Prodigy: GE Healthcare, Milwaukee, USA) to determine lean mass and fat mass. For the calf, total body scans were analysed offline; a region of interest was placed over the calf area using the tibial plateau and the tip of the lateral malleous as landmarks. All DXA studies and offline assessment were performed by a single observer. 2.5. Phosphorus magnetic resonance spectroscopy Phosphorus magnetic resonance spectroscopy was used to non-invasively assess skeletal muscle metabolism at rest, during exercise and recovery. The scanning sequence is described in more detail within Online Supplementary Methods. Spectra were quantified using the Java-based magnetic resonance user interface (jMRUI version 2.0, EU Project) to obtain relative concentrations of inorganic phosphate, phosphocreatine (PCr) and ATP. Kinetics of post exercise PCr recovery was assessed by least-squares fit of PCr relative signal intensity time course to an exponential function. Because pH changes during exercise were minimal, the exponential rate constant of PCr recovery, k, can be taken as a measure of overall muscle mitochondrial capacity, an integrated system property depending on intrinsic mitochondrial numbers and function and on cardiovascular delivery of substrate and oxygen to the muscle. 2.6. Cardiac magnetic resonance imaging MR imaging was performed using a 1.5 T MR scanner (Philips Medical Systems, Best, The Netherlands) equipped with a 5-ch cardiac receive coil and a dedicated MR workstation (Philips Medical Systems). Detailed methodology for assessment of ventricular volumes and function together with flow quantification is included in the Supplementary Online Material. 2.7. Free breathing real-time magnetic resonance imaging Prior to entering the magnet subjects were taught to perform a Valsalva manoeuvre through instruction and demonstration and trialled on CPAP (method outlined in Supplementary Material along with detailed explanation of FBMR scanning methodology). Real-time flow measurements [2] were performed in the sequence of SVC, aorta then IVC at rest, during a Valsalva manoeuvre, after 2 min of CPAP and then during exercise. Each set of data consisted of 200 consecutive, real-time (no ECG-triggering), phase-contrast, 43 ms flow acquisitions. This equated to 8.6 s of flow data. ECG and respiratory waveforms were simultaneously collected and saved for off-line analysis.
Table 1 Patient characteristics. Trainers (n = 6) Age (years) Sex Type of repair
31 +/− 4 1 female, 5 male 2 APC, 3 intracardiac TCPC (1 with fenestration), 1 extra-cardiac conduit (converted from APC) NYHA class 3 NYHA I, 3 NYHA II Sats (%) 97 +/− 1 Age at first surgery (years) 11 +/− 4 Time since last Fontan repair (years) 21 +/− 1 Ventricular function at echocardiography 3 normal, 2 mild impairment, 1 mild–moderate impairment 2 27 +/− 1 Body mass index (kg/m )
Non-trainers (n = 5) 32 +/− 1 1 female, 4 male 2 APC, 2 intracardiac TCPC, 1 extra-cardiac conduit 3 NYHA I, 2 NYHA II 99 +/− 1 12 +/− 2 18 +/− 2 2 normal, 2 mild impairment, 1 mild–moderate impairment 25 +/− 1
Data are mean +/−SEM. Abbreviations: APC—atriopulmonary connection and TCPC—total cavopulmonary connection.
Please cite this article as: Cordina RL, et al, Resistance training improves cardiac output, exercise capacity and tolerance to positive airway pressure in Fontan physiology, Int J Cardiol (2012), http://dx.doi.org/10.1016/j.ijcard.2012.10.012
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Fig. 1. Study design. Abbreviations: CPET—cardiopulmonary exercise testing, DXA—dual X-ray absorptiometry, FBMR—free breathing magnetic resonance imaging, MRI—magnetic resonance imaging and MRS—magnetic resonance spectrometry.
The exercise protocol consisted of low (0.5 Watts/kg) and moderate (0.75 Watts/kg) levels of exercise. We did not include higher intensity exercise in the protocol as excessive movement degraded the quality of the data. Subjects exercised for 3 min before data acquisition commenced to ensure they had reached steady state and continued to exercise during scanning. There was a 3-min rest period between exercise cycles. Subjects that had repeat testing pedalled at the same cadence (regulated through verbal prompting from the study supervisor) and workload for subsequent tests. 2.7.1. MRI data calculations ECG and respiratory data were combined with relevant flow data offline. Respiratory rate and heart rate were calculated for each data set. Mean flow values were calculated over 2 breaths unless due to low respiratory rate a full data set could not be obtained over the 8.6 s scanning time, in which case just one breath was used. Inspiration was taken from the point of upstroke on the respiratory curve and expiration from the point of decline. For caval flow mean, inspiratory and expiratory blood flows were calculated. Where dual SVCs were present (n=2) total SVC flow was used. Aortic data was used to calculate mean flow and mean stroke volume, peak-expiratory flow, peak-expiratory stroke volume, trough-inspiratory flow and trough-expiratory stroke volume. Calculations account for regurgitant flow or volume and report net forward flow or stroke volume. Flow data were obtained during phase 2 of the Valsalva manoeuvre when flow was at its lowest; these values were calculated over 3 heart beats. From aortic flows the respiratory-dependent component of stroke volume was calculated as follows:
ðpeak expiratory stroke volume−trough inspiratory stroke volumeÞ: For venous flow we also calculated a respiratory dependent fraction using flow and volume calculations. The difference between inspiratory and expiratory flows was considered to represent the portion of flow that depended upon respiration [12].
The respiratory-dependent flow factor was calculated as follows: ðinspiratory flow−expiratory flowÞ=mean flow: Inspiratory and expiratory volumes were treated similarly with the respiratorydependent blood volume factor calculated using the equation: ðinspiratory volume−expiratory volumeÞ=total volume where blood volumes were calculated from the area under the flow curve occurring during the cardiac or relevant phase of respiratory cycle. One subject's SVC data was excluded from analysis as he had a small arteriovenous shunt close to the pulmonary anastmosis, seen at cardiac MRI. Combined resting SVC and IVC flow differed 6.6% from mean aortic flow similar to previously reported values [2]. The difference between exercise measurements was 13.1%. 2.8. Strength training Training subjects underwent a regimen of high-intensity total body resistance training with a focus on calf muscle strengthening, 3 days per week for 20 weeks after baseline strength testing. Exercises included the chest press, lat (latissimus dorsi) pull-down alternating each session with seated row, leg press, knee extension, knee flexion, hack calf and seated calf (Keiser Sports Health Equipment, California, USA). Strength testing and training techniques are described in detail in Supplementary Material. Subjects were trained in weight-lifting technique; straining with a Valsalva during a lift was discouraged and they were taught to exhale through the strain to avoid a marked reduction in cardiac output. Participants performed 3 sets of 8 repetitions on each machine. Each session lasted approximately 60 min. All sessions were carefully supervised with one trainer per 3 subjects at most.
Please cite this article as: Cordina RL, et al, Resistance training improves cardiac output, exercise capacity and tolerance to positive airway pressure in Fontan physiology, Int J Cardiol (2012), http://dx.doi.org/10.1016/j.ijcard.2012.10.012
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There were 3 drop-outs from the training group. One training subject decided the commitment to training was too great after attending 3 training sessions and withdrew from the study, another suffered a transient ischemic episode over a weekend, 3 days after his most recent training session. He commenced anticoagulation and suffered from substantial nose-bleeds as a result before training had resumed. Although the risk of bleeding related to strain during weight lifting was considered small he was withdrawn from the study. The final drop-out occurred towards the end of training. He moved to a rural area and was unable to continue attending the gymnasium sessions as a result. Two non-training Fontan subjects did not return for follow-up testing. 2.9. Statistical analysis The prespecified primary study end-point was change in peak VO2 after strength training. Other parameters were not adjusted for multiple comparisons as they were exploratory variables to understand mechanisms of any observed change in exercise performance such as stroke volume, cardiac output and respiratory dependence. All variables are expressed as mean +/− SEM. Within subject comparisons were analysed by paired Student's t tests. For between group analysis unpaired Student's t tests were employed. SPSS statistics Data Editor (IBM Corporation, New York, USA) was used for statistical calculations. A two-tailed p-value ≤0.05 was considered statistically significant.
3. Results 3.1. Study group characteristics Subject characteristics are summarised in Table 1. The 4 male and 2 female Fontan subjects who underwent MRS testing, were aged 32+/−4 years and for sex-matched controls age was 33+/− 3 years (p=NS). For free breathing MRI, mean age of the all-male Fontan subgroup was 29+/−5 years, body surface area (BSA) was 2.05+/− 0.07 m2 in the trained state and 2.02+/−0.09 m2 in the detrained state, total body lean mass percentage was 67+/−1% in the trained state and 65+/−1% in the detrained state. In comparison, for the sex-matched controls age was 34+/−5 years, BSA was 1.90+/− 0.07 m2 and total lean mass was 67+/−0% (p=NS for all). Mean time to follow-up was 21+/−1 weeks in the training group and 19+/−1 weeks in the non-trainers. The detraining period was 56+/− 2 weeks. No alterations in pharmacotherapy occurred for any Fontan subject during the study. Anatomical characteristics are described in Table 2. 3.2. Cardiac magnetic resonance imaging
4.0% and atrioventricular valve regurgitant fraction was 5+/−2% (detailed flow data is not shown). 3.3. Strength training For the 6 subjects completing the 20-week training programme 43 +/− 3 training sessions were attended per subject and gym attendance was 76 +/− 5%. Strength increased by 43 +/− 7% (p = 0.002) with training. There were no cardiac arrhythmia events observed during the programme or other reported cardiac events apart from the subject described in Section 2.8. 3.4. Body composition scanning Results of trainers compared with non-trainers are shown in Fig. 2a (1.94+/− 0.52 vs. −0.80 +/− 0.36 kg, p = 0.003 for total body lean mass and 101 +/− 15 vs. −19+/− 26 g, p =0.002 for non-dominant calf lean mass, n= 11 for both). Following the 12-month detraining period total body lean mass fell from 56.3+/− 2.7 kg to 53.1+/− 2.5 kg (n=4, p = 0.03) and calf lean mass fell from 2353 +/− 183 g to 2254+/− 197 g (n= 4, p =0.03). Overall body weight fell after detraining (84.8 +/− 5.6 vs. 82.6 +/− 5.1 kg, p = 0.05). 3.5. Cardiopulmonary exercise testing At baseline, peak VO2 was 71+/−6% of predicted normal values in the training group and 60+/−19% in the non-trainers (p=NS). Training was associated with a significant increase in peak VO2 (see Fig. 2b; Δ183+/−31 vs. 5+/−39 ml/min, p=0.02 equivalent to Δ9.5+/−2.4 vs. 1.4+/−2.9% from baseline, p=0.03, n=10 for both). In terms of percent predicted values, trainers' VO2 increased by 7+/−2% compared with 1+/−1% in non-trainers (p=0.01, n=10). Other peak exercise parameters were altered but not significantly so; Δ workload 9.8+/−4.7 vs. −0.2+/−3.5 Watts, p=0.128, Δ heart rate −2+/−3 vs. 2+/− 2 bpm, p=0.368, Δ carbon dioxide output (VCO2) 141+/−83 vs. −33+/−82 ml/min, p=0.172, Δ minute ventilation (Ve) 8.0+/−4.9 vs. 2.5+/−3.4 l/min, p=0.388, Δ respiratory quotient −0.03+/−0.04
Five subjects from the training group underwent testing at baseline. Stroke volume was 97.2+/−7.2 ml, ejection fraction was 51.8+/− 2.6%, cardiac output was 7.5+/−0.8 l/min, aortic valve regurgitant fraction was 11.7+/−3.5% and atrioventicular valve regurgitant fraction was 11.0+/−4.6%. Of the non-trainers only 2 had testing; stroke volume was 90.5+/−15.5 ml, ejection fraction was 44.0+/−5.0%, cardiac output was 6.2+/−0.5 l/min, aortic valve regurgitant fraction was 16.0+/− Table 2 Anatomical characteristics. Training subjects 1. 2. 3. 4. 5. 6.
Tricuspid atresia Dextrocardia, tricuspid atresia, VSD, subpulmonary stenosis and TGA DILV, hypoplastic tricuspid valve and subpulmonary stenosis Dual-SVC, mitral atresia, VSD and TGA HLHS, VSD, subpulmonary stenosis and TGA Dual-SVC, VSD, DORV, pulmonary stenosis
Non-training subjects 1. 2. 3. 4. 5.
Tricuspid atresia, subpulmonary stenosis and TGA Hypoplastic right ventricle, tricuspid valve and pulmonary valve, VSD and TGA Dextrocardia, DILV, pulmonary atresia DORV Dextrocardia, right AV-valve atresia, cc-TGA, DORV and pulmonary stenosis
Abbreviations: AV—atrioventricular, cc-TGA—congenitally corrected transposition of the great arteries, DILV—double inlet left ventricle, DORV—double outlet right ventricle, HLHS—hypoplastic left heart syndrome, SVC—superior vena cava, TGA—transposition of the great arteries, and VSD—ventricular septal defect.
Fig. 2. Change in lean mass and peak VO2 with resistance training versus non-training controls. Error bars shown are SEM. Abbreviations: VO2 oxygen uptake.
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vs. −0.04+/−0.03, p=0.726, Δ oxygen pulse 1.2+/−0.7 vs. −0.02+/−0.2 ml/beat, p=0.133, Δ anaerobic threshold 21+/−9 vs. 3+/−8 Watts, p=0.15. There was no significant difference between trainers and non-trainers when CPET data were analysed at 0.8 isotime (detailed data not shown).
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The results observed following the 12-month detraining period are shown in Fig. 3a–b (peak VO2: 2.4+/−0.2 vs. 1.9+/−0.2 l/min, pb 0.001, peak VCO2: 2.7+/−0.2 vs. 2.2+/−0.2, pb 0.001, peak Ve: 102.6+/−17.7 vs. 79.1+/−15.6 l/min, p=0.01, oxygen pulse: 14.7+/−1.0 vs. 12.3+/−0.7 ml/beat, p=0.005, anaerobic threshold
Fig. 3. Trained state versus detrained state at exercise testing and during free-breathing magnetic resonance imaging. a and b: Cardiopulmonary exercise testing parameters; c: stroke volume; d: mean aortic flow; e: mean inferior vena caval flow; f: expiratory inferior vena caval flow; g: respiratory-dependence factor for inferior vena caval blood return. Error bars shown are SEM. Abbreviations: CPAP—constant positive airway pressure, IVC–inferior vena cava, VCO2—carbon dioxide production, Ve—minute ventilation, VO 2 oxygen uptake and W—Watts.
Please cite this article as: Cordina RL, et al, Resistance training improves cardiac output, exercise capacity and tolerance to positive airway pressure in Fontan physiology, Int J Cardiol (2012), http://dx.doi.org/10.1016/j.ijcard.2012.10.012
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Fig. 3 (continued).
144+/−12 vs. 118+/−15 Watts, p=0.05, peak workload: 173+/−15 vs. 149+/−19 Watts, p=0.01, n=4 for all). In terms of percent predicted values peak VO2 fell from 73+/−4 to 59+/−8% (pb 0.001, n=4). At 0.8 isotime, VCO2 was lower in the trained state at that workload (1.54+/−0.09 vs. 1.69+/−0.07 l/min, p=0.05, n=4).
3.7. Free breathing real-time magnetic resonance imaging
3.6. Phosphorus magnetic resonance spectroscopy
3.7.1. The Fontan circulation in the trained and untrained states versus normal controls Fontan subjects, in both the trained and detrained states, rely more heavily on inspiration for cardiac filling than normal controls; at rest, the respiratory dependent component of stroke volume was significantly greater in Fontan subjects (20.3+/− 2.5 vs. 5.5+/− 2.0 ml, p =0.004
Baseline MRS assessment suggested an impaired PCr recovery constant compared with normal controls (1.58+/−0.16 vs. 2.15+/− 0.20, p=0.06, n =6). Muscle aerobic capacity tended to improve with training (1.34+/− 0.13 vs. 1.63+/−0.14, p=0.09, n =4).
Adjustment of results for BSA did not alter statistical significance; results are reported as absolute measurements. Heart rates and respiratory rates recorded during testing are included in online Supplementary Material (Table A).
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lower in the detrained state (24.7+/− 10.4 vs. −1.2 +/− 5.0%, p= 0.07, n= 8) but not in the trained state (17.6+/− 15.0 vs. −1.2 +/− 5.0%, p =0.278, n= 8). During exercise, the increase in aortic flow from baseline at moderate levels of exertion was lower in Fontan subjects (44.3+/− 11.2 vs. 78.2+/− 10.8 ml/s, p = 0.07 in the trained state, 42.1+/− 5.8 vs. 78.2 +/− 10.8 ml/s, p = 0.03 in the detrained state). In keeping with aortic analysis, increased respiratory dependence was also observed in the IVC associated with reduced expiratory flows both at rest and exercise in both the trained and detrained states (see Table 3). In the SVC differences in flow between Fontan and normal subjects were only detectable during exercise (at 0.75 Watts/kg expiratory flow was less in Fontan subjects; 19.2+/− 3.3 vs. 37.2 +/− 3.7 ml/s trained state, 18.7 +/− 1.6 vs. 37.2+/− 3.7 ml/s detrained state, p = 0.01, n =7 for both). 3.7.2. The Fontan circulation in the trained versus detrained state Results are demonstrated in Fig. 3c–g. Stroke volume increased at rest (77.8 +/− 10.3 vs. 66.7 +/− 9.3 ml, p =0.01, n = 4) and during exercise (86.5+/− 10.7 vs. 72.2 +/− 7.8 ml at 0.5 Watts/kg, p =0.06 and 90.9 +/− 11.9 vs. 75.0+/− 10.2 ml at 0.75 Watts/kg, p =0.04, n=4 for both). Mean aortic flow was higher at rest and on CPAP (100 +/− 10 vs. 83 +/−10 ml/s, 101 +/− 17 vs. 77 +/−12 ml/s respectively, p = 0.03, n= 4 for both) and tended to be higher at low intensity exercise (130 +/− 18 vs. 108 +/− 11 ml/s, p= 0.06, n=4). Mean flow in the IVC was lower at rest (65 +/−8 vs. 53 +/−8 ml/s, p =0.007, n=4) with augmented expiratory IVC flow both at rest and during exercise (34 +/− 11 vs. 16 +/− 8 ml/s at rest, p = 0.04, 43 +/− 10 vs. 22+/− 6 ml/s at 0.5 Watts/kg, p = 0.02, 42 +/− 13 vs. 16 +/− 19 ml/s at 0.75 Watts/kg, p = 0.09, n = 4 for all). At rest there was no difference in the respiratory-dependent fraction of IVC blood return between the trained and detrained states (0.46 +/− 0.15 vs. 0.72 +/− 0.15, p = 0.16, n = 4) however there was a significant difference observed during exercise (Fig. 3g; 0.58+/−0.09 vs. 0.81+/−0.02 at0.5 Watts/kg, p=0.02, 0.62+/−0.08 vs. 0.88+/−0.16 at 0.75 Watts/kg, p=0.08, 0.60+/−0.16 vs. 0.84+/−0.21 for mean exercise, p=0.004, n =4 for all). The respiratory-dependent flow factor also improved in the trained
Table 3 Expiratory IVC flow and respiratory dependence in trained and detrained Fontan subjects versus normal controls.
Rest
Expiratory flow (ml/s)
Respiratory dependent volume factor CPAP
Expiratory flow (ml/s)
Respiratory dependent volume factor 0.5 Watts/kg
Fig. 3 (continued).
in the trained state; 20.1+/− 3.9 vs. 5.5 +/− 2.0 ml, p= 0.02 in the detrained state, n =8). On CPAP the peak expiratory stroke volume (compared with peak rest values) tended to fall more in the detrained state (8.4 +/−2.6 vs. 0.8+/− 2.3%, p =0.07, n = 8); this tendency was not observed in the trained state (1.2 +/−5.9 vs. 0.8 +/− 2.3%, p =0.946, n = 8). Furthermore during a Valsalva manoeuvre, stroke volume also tended to be
Expiratory flow (ml/s)
Respiratory dependent volume factor 0.75 Watts/kg
Expiratory flow (ml/s)
Respiratory dependent volume factor
Trained state
Detrained state
33.6 +/−10.5 vs. 53.4 +/−4.3 p = 0.14 0.46 +/−0.15 vs. 0.03 +/−0.15 p = 0.09 18.9 +/− 9.3 vs. 53.2 +/− 9.0 p = 0.04 0.73 +/− 0.13 vs. 0.26 +/− 0.19 p = 0.08 42.6 +/− 10.2 vs. 93.8 +/− 9.3 p = 0.01 0.58 +/− 0.09 vs. 0.08 +/− 0.08 p = 0.006 42.4 +/− 12.9 vs. 110.5 +/−4.6 p = 0.008 0.62 +/− 0.08 vs. 0.07 +/− 0.11 p = 0.01
16.0 +/− 7.8 vs. 53.4 +/− 4.3 p = 0.006 0.72 +/− 0.15 vs. 0.03 +/− 0.15 p = 0.02 15.6 +/− 7.4 vs. 53.2 +/− 9.0 p = 0.02 0.88 +/− 0.05 vs. 0.26 +/− 0.19 p = 0.02 22.1 +/− 6.2 vs. 93.8 +/− 9.3 p = 0.001 0.81 +/− 0.06 vs. 0.08 +/− 0.08 p b 0.001 15.5 +/− 18.7 vs. 110.5 +/− 4.6 p = 0.008 0.88 +/− 0.16 vs. 0.07 +/− 0.11 p = 0.01
Abbreviations: CPAP—constant positive airway pressure, and IVC—inferior vena cava. Significant results (p b 0.05) are shown in bold text.
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state compared with the detrained state (0.53 +/−0.07 vs. 0.76 +/− 0.08, p =0.009 at rest, 0.49+/− 0.08 vs. 0.69+/− 0.06, p =0.004 at 0.5 Watts/kg, 0.58 +/− 0.07 vs. 0.81 +/− 0.23, p = 0.269 at 0.75 Watts/kg, n = 4 for all). By contrast, analysis of data obtained from the SVC did not reveal any differences between the trained and detrained states.
4. Discussion In this study of exercise pathophysiology in the setting of the Fontan circulation, we have found that isolated muscle resistance training (without additional aerobic training) significantly increases exercise capacity. In exploring potential mechanisms, we found that augmenting peripheral muscle is associated with improvements in cardiac filling and cardiac output at rest, exercise and during inspiratory stress as well as reduced dependence on respiration for blood to return to the heart via the IVC. We postulate that these physical changes are due to increased muscle bulk and improvement of the peripheral muscle pump. In the normal circulation, higher peripheral muscle bulk reduces venous compliance at rest and, as a result, increases preload with resulting elevations in stroke volume and cardiac output [11,14–16]. Our data suggest that the same may be true in the Fontan circulation; post-training subjects, at rest, had increased IVC flow, stroke volume and cardiac output. In addition, increased IVC flow was seen during expiration, presumably also through augmentation of peripheral muscle bulk. This resultant increase in expiratory IVC flow meant reduced respiratory dependence with improved cardiac performance during a Valsalva manoeuvre and CPAP; two situations that attenuate negative intrathoracic pressure important for cardiac filling in the Fontan circulation. Exercising muscles pump blood into the venous system. Furthermore, peripheral muscle training results in increased vascularization of targeted muscle-groups [17] leading to greater “stroke volume” from exercising muscles with each movement [18,19]. This, in addition to the effects described at rest, may be another contributor to the improved cardiac output and stroke volume during exercise observed post-training in our study. Oxygen pulse data obtained from CPET in our subjects support the concept that improved cardiac stroke volume in the trained state contributed to better exercise performance. Traditionally, intensive strength training has been discouraged in cardiac disease although it has emerged as an important component of cardiac rehabilitation [20]. Straining during weight training is potentially associated with marked elevations in blood pressure [21] and subjects with a Fontan circulation are particularly susceptible to falls in cardiac output during a Valsalva manoeuvre, commonly performed during heavy weightlifting. We educated our training subjects appropriately and did not encounter any significant cardiovascular events during the programme; training sessions were carefully supervised. To our knowledge, isolated strength training to enhance exercise performance in subjects palliated with a Fontan procedure has not previously been investigated and a documented improvement in exercise performance through any type of training programme (that has included a control group for comparison) has not been reported. Brassard et al. [22,23] described the effects of a combined aerobic and light-resistance training programme in Fontan subjects compared with a control-Fontan group. They did not observe a significant improvement in peak VO2 following the 8-week regimen however an improvement in skeletal muscle ergoreceptor function was reported. We also observed alterations in muscle function; a shift in anaerobic threshold and MRS results suggested improved skeletal muscle aerobic function with training, another novel finding from this current report. A small number of other studies have shown improvements in exercise performance and oxygen pulse through aerobic training with uncontrolled study design in largely paediatric populations that have included some young adults [23–25]. It is well-recognised that improved strength is associated with higher levels of performance in health and disease [22,26] but our findings suggest
that, in the Fontan group, gains in strength are also associated with improved cardiac filling and output. In elegant studies, Hjortdal et al. [2] demonstrated the respiratory dependence of the Fontan circulation, using free breathing MRI. They also described an attenuation of respiratory dependence during lower limb exercise, suggesting that a peripheral pump could contribute to some of the work usually done by the respiratory bellows. Our findings extend these short-term findings and demonstrate that augmentation of peripheral muscle bulk may reduce the respiratory dependence for cardiac filling. In addition, a reduction in respiratory dependence likely reduces the work of breathing. Direct measurement of breathing work is invasive and therefore we did not include it in our study protocol but studies have shown that increased work of breathing leads to compromised locomotor blood flow and cardiac function both in health and heart failure [27]. This may be an additional mechanism whereby strength training could be beneficial for Fontan subjects. It is widely known that subjects with the Fontan circulation tolerate positive pressure ventilation poorly, as attenuation of negative intrathoracic pressure decreases cardiac filling [28]. For the first time we have demonstrated that augmentation of the peripheral muscle pump is associated with improved cardiac output during CPAP, which is of potential clinical significance considering the risk of reduced cardiac output during general anaesthesia, in Fontan subjects [3,29]. Limitations of our study include the lack of baseline FBMR data due to technical difficulties initially encountered. Nevertheless, we have information from two distinct untrained states; baseline and 12 months post-training cessation. Whilst the detraining period became necessary due to these technical issues, the additional information obtained enhances confidence that the changes seen post-training were indeed due to the training related increase in peripheral muscle mass. Our study was also limited by small numbers; this was in part, due to the time commitment required for the training programme and the need to live in close proximity to the training facility. In conclusion, our research suggests that strength training is safe and may have important benefits for cardiac function and exercise performance in subjects with the Fontan-type circulation. Strength training to augment peripheral muscle bulk may be an important component of routine management in this group and warrants further investigation.
Conflict of interest Carsten Liess is employed as a clinical scientist with Philips Healthcare. We did not acquire external funding for this project. All authors approve submission.
Acknowledgements The authors wish to thank their enthusiastic study participants, Mr Rowley Hilder for constructing the MRI ergometer and output system and A/Professor David Richmond for his considerate comments on the manuscript. Dr Jennifer Alison and Mr Phillip Munoz, Royal Prince Alfred Hospital, Sydney, Australia for providing expert advice in the area of exercise physiology, Mr Nathan Malitz and Mrs Helen Lackey, Specialist Magnetic Resonance Imaging, Sydney, Australia and Mr Ken Rayner and Mr Daniel Moran, Diagnostic Medical Services, Neuroscience Research Australia, for expert radiography, the staff at the STRONG Clinic, Balmain Hospital for sharing their expertise in resistance training and Dr Craig Phillips and Mr George Dungan, Woolcock Institute, Sydney, Australia for lending expertise in non-invasive ventilation. The MRUI software package was kindly provided by the participants of the EU Network programmes: Human Capital and Mobility, [CHRX-CT94-0432] and Training and Mobility of Researchers, [ERB-FMRX-CT970160].
Please cite this article as: Cordina RL, et al, Resistance training improves cardiac output, exercise capacity and tolerance to positive airway pressure in Fontan physiology, Int J Cardiol (2012), http://dx.doi.org/10.1016/j.ijcard.2012.10.012
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Please cite this article as: Cordina RL, et al, Resistance training improves cardiac output, exercise capacity and tolerance to positive airway pressure in Fontan physiology, Int J Cardiol (2012), http://dx.doi.org/10.1016/j.ijcard.2012.10.012