Abstract
Background:
Patients with Fontan palliation have reduced aerobic capacity because of impaired cardiac, pulmonary, and skeletal muscle function. However, the assessment of aerobic capacity in this population still relies on comparisons with people without cardiovascular disease, rather than comparison with the expected aerobic capacity of other Fontan patients. The purpose of this study was to determine the expected aerobic capacity of adults with Fontan palliation.
Method:
Adults with Fontan palliation that underwent cardiopulmonary exercise test at Mayo Clinic (2003–2023) were stratified into quartiles based on the predicted peak VO2. We assessed correlates of predicted peak VO2, and the relationship between predicted peak VO2 quartiles and cardiovascular outcomes (death/transplant).
Results:
Of 323 patients (age 29±9 years; 177 [55%] men), median peak VO2 was 19.1 [15.2 – 23.9] ml/kg/min, and this corresponds to a predicted peak VO2 of 51% [range 19 −88; interquartile range 41 – 62]. After multivariable adjustments, the correlates of predicted peak VO2 were body mass index (β±SE −2.61±0.95; 2.61% decrease in predicted peak VO2 per 5 kg/m2 increase in body mass index, p=0.009), systemic saturation (β±SE 3.65±0.85; 3.65% increase in predicted peak VO2 per 5% increase in oxygen saturation, p<0.001), and Fontan pressure (β±SE −1.24±0.22; 1.24% decrease in predicted peak VO2 per 1 mmHg increase in Fontan pressures, p<0.001). There was a 47% increase in the risk for death/transplant from a higher predicted peak VO2 quartiles to next lower quartile (adjusted HR 1.47, 95% CI 1.09–2.05, p=0.01).
Conclusions:
The results of the current study would help calibrate interpretation of exercise test data in adults with Fontan palliation and improve risk stratification in this population. It also underscores the need to maintain normal Fontan hemodynamics and body weight, which are important determinants of aerobic capacity.
Keywords: Fontan physiology, Aerobic capacity, Risk stratification
INTRODUCTION
The assessment of peak oxygen consumption (VO2) during cardiopulmonary exercise testing provides a measure of aerobic capacity and it is used for risk stratification in patients with cardiovascular disease.1–5 The peak VO2 during exercise is dependent on cardiac output reserve, pulmonary function, and skeletal muscle function, and therefore provides an assessment of the composite function and interaction of these organ-systems.1–5 Peak VO2 varies by age, sex, and body size, and hence it is often expressed as % of predicted (%-predicted), in reference to the expected aerobic capacity of a person of similar age, sex, and body size without cardiovascular disease.6
Patients with Fontan palliation have reduced aerobic capacity, and this is expected because patients with Fontan palliation commonly have impaired cardiac, pulmonary, and skeletal muscle function; the organ-systems that determine aerobic capacity.7–15 However, the assessment of aerobic capacity in this population still relies on comparisons with age and sex matched control group of people without cardiovascular disease.7–15 Since reduced aerobic capacity is to be expected in patients with Fontan palliation, it may be more helpful to interpret the aerobic capacity of a patient with Fontan palliation relative to what would be expected of other patients with similar physiology.15 However, such data are currently lacking. Our study objectives were: (1) To determine the expected aerobic capacity of adults with Fontan palliation (as measured by predicted peak VO2), and to stratify the cohort into quartiles of the expected predicted peak VO2. (2) To identify clinical and hemodynamic correlates of predicted peak VO2. (3) To determine the relationship between predicted peak VO2 quartiles and cardiovascular outcomes (defined as the composite outcome of all-cause mortality and/or heart transplantation).
METHODS
Study Population
The data, analytic methods, and study materials will be made available to other researchers for purposes of reproducing the results or replicating the procedure upon request to the corresponding author. This is a retrospective cohort study of adults (age ≥18 years) with Fontan palliation that underwent cardiopulmonary exercise test using treadmill ergometer at Mayo Clinic from January 1, 2003, and December 31, 2023. The first cardiopulmonary exercise test performed within the study period was considered as the baseline exercise test and used to determine the aerobic capacity of each patient. The clinical indices and cardiac imaging obtained within 6 months from the baseline exercise test were used to define the baseline characteristics of the cohort. Similarly, cardiac catheterizations performed within 12 months from the baseline exercise test were retrieved and analyzed for the study. The clinical data reviewed include anatomic/surgical history, cardiac medications, laboratory data, echocardiography, cardiac magnetic resonance imaging, and cardiac catheterization report. The Mayo Clinic Institutional Review Board approved this study and waived informed consent for patients that provided research authorization.
Cardiopulmonary Exercise Testing
All patients underwent cardiopulmonary exercise test with a treadmill ergometer using the modified Bruce protocol, and only the patients that achieved maximum effort during exercise test, defined as respiratory exchange ratio >1.1, were included in the study.16,17 The technical details for performing cardiopulmonary exercise test in adults with congenital heart disease at this institution have been described.7,18 In brief, breath-by-breath expiratory gas analysis were performed using a CardiO2 exercise testing system (Medical Graphics Corp, Minneapolis, MN).19 Peak VO2 was defined as the highest VO2 detected during the test, and was expressed in ml/kg/min, as well as %-predicted value for age and sex. Predicted peak VO2 was determine using the FRIEND registry equation: Predicted peak VO2 = VO2 max (ml·kg−1·min−1) = 79.9 – (0.39 × age) – (13.7 × gender [0=male; 1=female]) − (0.127 × weight[lbs]).20 Normal aerobic capacity was defined as predicted peak VO2 >80%.13
Statistical Analysis
Data were presented as mean ± standard deviation, median (interquartile range [IQR]), and count (%). Normality was assessed using Shapiro-Wilk test of normality. The patients were stratified into quartiles based on the predicted peak VO2 from the baseline exercise test. The baseline clinical characteristics between the quartiles were compared using the Cochrane-Armitage Trend Test for categorical variables, and comparison of means for continuous variables to determine trend across the quartiles.
The correlates of predicted peak VO2 were assessed using linear regression. First, we assessed the correlations between predicted peak VO2 and the following clinical variables: demographic indices, anatomic/surgical indices, comorbidities, echocardiographic indices of ventricular and valvular function, cardiac magnetic resonance imaging derived ventricular volumes and ejection fraction, and invasive hemodynamic indices. The variables with p<0.1 on univariable analysis, were then used to create a multivariable model based on stepwise backward selection, with a p<0.1 required for a covariate to remain in the model.
The occurrence of death/transplant was assessed as time-to-event outcome from the time of baseline exercise test to the occurrence of event, last clinical encounter, or December 31, 2023. Survival curves were constructed using the Kaplan Meier method and the cumulative incidence of death/transplant across the predicted peak VO2 quartiles were compared using log-rank test. The correlates of death/transplant were assessed using multivariable Cox regression models, using similar covariate selection criteria as described above for the linear regression models. Conditional imputation was used to address missing variables.21 All statistical analyses were performed with BlueSky Statistics software (version. 7.10; BlueSky Statistics LLC, Chicago, IL, USA), and JMP statistical software (version 17.1.0, JMP Statistical Discovery LLC, NC). P value <0.05 was considered to be statistically significant for all analyses.
RESULTS
Baseline Characteristics
Of 555 adults with Fontan palliation, 323 (58%) met the study inclusion criteria. Table 1 shows a comparison of the baseline characteristics of the 323 patients included in the study versus the 232 patients that were excluded. The study cohort had a lower body mass index and prevalence of atrial fibrillation, but otherwise there were no other significant differences in baseline characteristics between the 2 groups (Table 1).
Table 1:
Baseline Characteristics
| CPET (N=323, 58%) | No CPET (N=232, 42%) | P | |
|---|---|---|---|
| Age, years | 29±9 | 30±9 | 0.521 |
| Male sex | 177 (55%) | 129 (56%) | 0.883 |
| Body surface area, m2 | 1.79 ±0.22 | 1.74 ±0.25 | 0.014 |
| Body mass index, kg/m2 | 23.5 ±3.6 | 24.8 ±4.1 | 0.032 |
| Systemic oxygen saturation, % | 93 [90,95] | 92 [89,94] | 0.431 |
| CIED | 70 (22%) | 56 (24%) | 0.374 |
| Anatomic data | |||
| Systemic left ventricle | 226 (70%) | 156 (67%) | 0.513 |
| CHD diagnosis | 0.631 | ||
| Tricuspid atresia | 90 (28%) | 59 (25%) | |
| Double inlet left ventricle | 51 (16%) | 39 (17%) | |
| Hypoplastic left heart syndrome | 39 (12%) | 36 (16%) | |
| Pulmonary atresia | 37 (12%) | 32 (14%) | |
| Unbalanced AV canal defect | 32 (10%) | 22 (10%) | |
| Double outlet right ventricle | 25 (8%) | 18 (8%) | |
| Others | 49 (15%) | 26 (11%) | |
| Surgical history | |||
| Type of initial Fontan connection | 0.194 | ||
| Atriopulmonary Fontan | 111 (34%) | 72 (31%) | |
| Lateral tunnel/IAC Fontan | 88 (27%) | 57 (25%) | |
| Extracardiac conduit Fontan | 124 (38%) | 103 (44%) | |
| Age at Fontan operation, years | 5 (3–8) | 6 (3–8) | 0.422 |
| Subsequent Fontan conversion | 89 (28%) | 56 (24%) | 0.378 |
| Comorbidities | |||
| Atrial arrhythmias | |||
| Atrial flutter/tachycardia | 100 (31%) | 79 (34%) | 0.423 |
| Atrial fibrillation | 59 (18%) | 63 (27%) | 0.014 |
| CKD III-V | 19 (6%) | 21 (9%) | 0.238 |
| Cirrhosis | 79 (25%) | 46 (20%) | 0.224 |
| Laboratory data | |||
| NTproBNP, pg/ml | 179 [74, 459] | 251 [93, 658] | 0.061 |
| Estimated GFR, ml/min/1.73 m2 | 95 [76,111] | 89 [72,109] | 0.174 |
| Hemoglobin, g/dl | 15.1±2.0 | 14.7±2.7 | 0.083 |
| Echocardiography | |||
| Estimated ventricular ejection fraction | 49 [43, 56] | 51 [44, 58] | 0.818 |
| ≥ Mod systemic AV valve regurgitation | 45 (14%) | 36 (16%) | 0.423 |
| Cardiac MRI | |||
| Ventricular EDV index, ml/m2 | 97±34 | 94±29 | 0.737 |
| Ventricular ESV index, ml/m2 | 51±22 | 49±18 | 0.622 |
| Ventricular SV index, ml/m2 | 46±19 | 43±17 | 0.288 |
| Ventricular ejection fraction | 52±13 | 50±16 | 0.459 |
| Cardiac catheterization | |||
| Fontan pressure, mmHg | 14 [12, 17] | 15 [13–19] | 0.133 |
| PAWP, mmHg | 9 [7, 12] | 10 [8, 13] | 0.221 |
| Transpulmonary gradient, mmHg | 5 [3, 8] | 5 [2,7] | 0.443 |
| PVR index, WU*m2 | 1.92 [1.46, 2.62] | 2.14 [1.53, 2.63] | 0.564 |
| Qs index, l/min/m2 | 2.24 [1.79, 2.72] | 2.30 [1.82, 2.70] | 0.831 |
Abbreviations: AV: Atrioventricular; CHD: Congenital heart disease; CKD: Chronic kidney disease; CPET: Cardiopulmonary exercise test; CIED: Cardiac implantable electronic device; EDV: End-diastolic volume; ESV: End systolic volume; GFR: IAC: Intra-atrial conduit; MRI: Magnetic resonance imaging; NTproBNP: N terminal pro hormone brain natriuretic peptide; PAWP: Pulmonary artery wedge pressure; PVR: Pulmonary vascular resistance; Qs: Systemic blood flow; SV: Stroke volume;
Data are presented as mean ± standard deviation and median [lower quartile, upper quartile] for continuous variable with normal versus skewed distribution, respectively, and as count (%) for categorical variables. Between-group comparisons were based on unpaired t-test and Wilcoxon rank sum test for continuous variables, and Fisher’s exact test and goodness of fit test for categorical variables.
Of the 323 patients in the study, the average age at the time of cardiopulmonary exercise test was 29±9 years, and 177 (55%) were males. The most common congenital heart disease diagnoses were tricuspid atresia (N=90, 28%), double inlet left ventricle (N=51, 16%), hypoplastic left heart syndrome (N=39, 12%), and pulmonary atresia (N=37, 12%). Overall, 226 (70%) patients had systemic left ventricle morphology. The types of Fontan connection were atriopulmonary Fontan connection (N=111, 34%), lateral tunnel/intra-atrial conduit Fontan (N=88, 27%), and extracardiac conduit Fontan (N=124, 38%), Table 1.
Aerobic Capacity
By design, all patients achieved maximum effort during exercise test. The median peak VO2 was 19.1 [IQR 15.2, 23.9] ml/kg/min, and this corresponds to a predicted peak VO2 of 51% [range 19 – 88; IQR 41, 62]. Table 2 shows the exercise test data of the cohort. Of note, only 5 of 323 (2%) patients had normal aerobic capacity defined as peak VO2 >80%.
Table 2:
Cardiopulmonary Exercise Test Indices
| N=323 | |
|---|---|
| Demographic indices | |
| Age, years | 29±9 |
| Male sex | 177 (55%) |
| Body surface area, m2 | 1.79 ±0.22 |
| Body mass index, kg/m2 | 23.5 ±3.6 |
| Exercise data | |
| Exercise time, minutes | 6.3±1.9 |
| Respiratory exchange ratio | 1.19±0.11 |
| Peak VO2, mL/kg/min | 19.1 [15.2, 23.9] |
| Percent predicted peak VO2, % | 51 [41, 62] |
| Metabolic equivalent | 6.2 [4.7, 7.3] |
| VE/VCO2 slope | 34.8±7.5 |
| Oxygen pulse, mL | 7.6±2.3 |
| Forced expiratory volume, L | 2.71±0.87 |
| Forced expiratory volume, % | 73±15 |
| Forced vital capacity, L | 3.36±1.02 |
| Forced vital capacity, % | 76±16 |
| Breathing reserve (%) | 52±16 |
| Oxygen saturation at rest, % | 93 [90, 95] |
| Oxygen saturation at peak exercise, % | 90 [86, 93] |
| Systolic blood pressure at rest, mmHg | 112±15 |
| Diastolic blood pressure at rest, mmHg | 73±13 |
| Systolic blood pressure at peak exercise, mmHg | 141±25 |
| Diastolic blood pressure at peak exercise, mmHg | 66±11 |
| Heart rate at rest, bpm | 79±14 |
| Heart rate at peak exercise, bpm | 136±31 |
| Heart rate at peak exercise, % | 79±25 |
| Heart rate recovery, bpm | 14±7 |
Abbreviations: VO2: Oxygen consumption; VE/VCO2: Ventilatory equivalent for carbon dioxide;
Data are presented as mean ± standard deviation and median [lower quartile, upper quartile] for continuous variable with normal versus skewed distribution, respectively.
Table 3 compares the baseline characteristics across the predicted peak VO2 quartiles. We observed higher body mass index, lower systemic oxygen saturation, greater use of loop diuretics, higher N-terminal prohormone brain natriuretic peptide, higher Fontan pressures and higher pulmonary artery wedge pressures in the lower quartiles of predicted peak VO2 (Table 3).
Table 3:
Baseline Characteristics Stratified by Predicted Peak Oxygen Consumption Quartiles
| Top Quartile (N=81) Peak VO2 63–88% | 2nd Quartile (N=81) Peak VO2 51–62% | 3rd Quartile (N=81) Peak VO2 41–50% | 4th Quartile (N=80) Peak VO2 19–40% | P | |
|---|---|---|---|---|---|
| Age, years | 28±9 | 28±7 | 31±10 | 29±9 | 0.191 |
| Male sex | 37 (46%) | 46 (57%) | 41 (51%) | 53 (66%) | 0.033 |
| Body surface area, m2 | 1.73±0.19 | 1.81±0.20 | 1.83±0.22 | 1.84±0.25 | 0.002 |
| Body mass index, kg/m2 | 22.9±3.7 | 23.8±4.5 | 24.9±4.8 | 25.1±4.3 | <0.001 |
| CIED | 16 (20%) | 17 (21%) | 15 (19%) | 22 (28%) | 0.261 |
| Anatomic data | |||||
| Systemic left ventricle | 61 (75%) | 53 (63%) | 54 (67%) | 58 (73%) | 0.463 |
| CHD diagnosis | 0.783 | ||||
| Tricuspid atresia | 25 (31%) | 23 (28%) | 22 (27%) | 20 (25%) | |
| Double inlet LV | 15 (19%) | 16 (20%) | 10 (12%) | 9 (11%) | |
| Double outlet RV | 5 (6%) | 5 (6%) | 6 (7%) | 9 (11%) | |
| Pulmonary atresia | 9 (11%) | 9 (11%) | 8 (10%) | 11 (14%) | |
| AV canal defect | 11 (14%) | 6 (11%) | 5 (6%) | 10 (13%) | |
| HLHS | 5 (6%) | 8 (10%) | 18 (22%) | 9 (11%) | |
| Others | 11 (14%) | 14 (17%) | 12 (15%) | 12 (15%) | |
| Surgical history | |||||
| Type of Fontan connection | 0.3 | ||||
| Atriopulmonary Fontan | 29 (36%) | 31 (38%) | 26 (32%) | 25 (31%) | |
| Lateral tunnel/IAC | 26 (32%) | 16 (20%) | 20 (25%) | 26 (33%) | |
| Extracardiac conduit | 26 (32%) | 34 (42%) | 35 (43%) | 29 (36%) | |
| Age at Fontan op, years | 4 (2–7) | 6 (3–8) | 5 (3–7) | 4 (2–7) | 0.33 |
| Fontan conversion | 20 (25%) | 25 (31%) | 21 (26%) | 23 (29%) | 0.31 |
| Vital signs | |||||
| Systolic BP, mmHg | 111±12 | 112±10 | 112±9 | 108±12 | 0.26 |
| Diastolic BP, mmHg | 67±9 | 70±10 | 69±8 | 66±11 | 0.38 |
| Pulse pressure, mmHg | 43±10 | 42±11 | 43±12 | 41±9 | 0.46 |
| Systemic saturation, % | 94 [92, 96] | 93 [91, 95] | 91 [88, 93] | 90 [86, 92] | <0.001 |
| Comorbidities | |||||
| Atrial arrhythmias | |||||
| Atrial flutter/tachycardia | 19 (23%) | 28 (25%) | 27 (33%) | 26 (33%) | 0.4 |
| Atrial fibrillation | 12 (18%) | 15 (19%) | 18 (22%) | 14 (18%) | 0.7 |
| CKD III-V | 1 (1%) | 5 (6%) | 6 (7%) | 7 (9%) | 0.12 |
| Cirrhosis | 18 (22%) | 15 (19%) | 17 (21%) | 29 (36%) | 0.05 |
| Medications | |||||
| Loop diuretics | 21 (26%) | 26 (32%) | 36 (44%) | 29 (61%) | <0.001 |
| Beta blockers | 33 (41%) | 28 (35%) | 30 (37%) | 37 (46%) | 0.542 |
| Calcium channel blockers | 7 (9%) | 7 (9%) | 5 (6%) | 8 (10%) | 0.763 |
| ACEI/ARB | 48 (59%) | 57 (70%) | 52 (64%) | 43 (54%) | 0.284 |
| MRA | 15 (19%) | 16 (20%) | 24 (30%) | 26 (33%) | 0.143 |
| Laboratory data | |||||
| NTproBNP, pg/ml | 128 [52, 248] | 165 [53, 439] | 215 [104, 574] | 299 [129, 1459] | 0.001 |
| GFR, ml/min/1.73 m2 | 95 [81, 117] | 90 [78, 109] | 90 [74–109] | 102 [73,112] | 0.532 |
| Hemoglobin, g/dl | 15.1±1.5 | 15.3±2.0 | 15.1±1.8 | 14.9±2.6 | 0.424 |
| Echocardiography | |||||
| Ventricular ejection fraction | 51 [45, 57] | 51 [44, 58] | 49 [45, 56] | 50 [45, 56] | 0.336 |
| ≥ Mod systemic AVVR | 9 (11%) | 8 (10%) | 12 (15%) | 16 (20%) | 0.254 |
| Cardiac MRI | |||||
| Ventricular EDVi, ml/m2 | 96±22 | 97±21 | 94±17 | 101±17 | 0.663 |
| Ventricular ESVi, ml/m2 | 46±16 | 51±18 | 48±20 | 57±16 | 0.684 |
| Ventricular SVi, ml/m2 | 49±15 | 46±17 | 43±16 | 44±22 | 0.382 |
| Ventricular ejection fraction | 53±14 | 50±18 | 51±15 | 47±18 | 0.264 |
| Cardiac catheterization | |||||
| Fontan pressure, mmHg | 12 [10, 15] | 13 [11,14] | 15 [12,17] | 15 [13, 18] | <0.001 |
| PAWP, mmHg | 8 [7,11] | 8 [7,11] | 11 [8,13] | 11 [9,14] | <0.001 |
| TPG, mmHg | 4 [2,6] | 5 [2,7] | 4 [2,7] | 4 [2,7] | 0.462 |
| PVR index, WU*m2 | 1.96 [1.21,2.34] | 1.78 [1.50,2.44] | 1.82 [1.49,2.68] | 2.10 [1.48,2.68] | 0.647 |
| Qs index, l/min/m2 | 2.25 [1.78, 2.64] | 2.20 [1.78, 2.65] | 2.23 [1.91, 2.95] | 1.98 [1.39, 2.64] | 0.572 |
Abbreviations: ACEI/ARB: Angiotensin-converting enzyme inhibitor/aldosterone receptor blocker; AV: Atrioventricular; AVVR: Atrioventricular valve regurgitation; BP: Blood pressure; CHD: Congenital heart disease; CPET: Cardiopulmonary exercise test; CIED: Cardiac implantable electronic device; EDVi: End-diastolic volume index; ESVi: End systolic volume index; HLHS: Hypoplastic left heart syndrome; IAC: Intra-atrial conduit; LV: Left ventricle; MRI: Magnetic resonance imaging; MRA: Mineralocorticoid receptor antagonist; NTproBNP: N terminal pro hormone brain natriuretic peptide; PAWP: Pulmonary artery wedge pressure; PVR: Pulmonary vascular resistance; Qs: Systemic blood flow; RV: Right ventricle; SV: Stroke volume; TPG: Transpulmonary gradient
P values represent test for trend across the 4 quartiles. Data are presented as mean ± standard deviation and median [lower quartile, upper quartile] for continuous variable with normal versus skewed distribution, respectively, and as count (%) for categorical variables.
Table 4 compares the baseline characteristics between males and females. Although males had higher peak VO2 in absolute terms compared to females (20.6 ml/kg/min [IQR 15.1, 25.6] versus 17.3 ml/kg/min [IQR 14.8, 20.8] for males and females, respectively, p=0.002), both groups had similar predicted peak VO2 (49% [IQR 39, 60] versus 52% [IQR 43, 62] for males and females, respectively, p=0.07).
Table 4:
Baseline Characteristics Stratified by Sex
| Male 177 (55%) | Female 146 (45%) | P | |
|---|---|---|---|
| Age, years | 29±9 | 30±9 | 0.224 |
| Age group | 0.787 | ||
| 18–30 years | 98 (55%) | 96 (49%) | |
| >30 years | 79 (45%) | 74 (51%) | |
| Peak VO 2 | |||
| Peak VO2 ml/kg/min | 20.6 [15.1, 25.6] | 17.3 [14.8, 20.8] | 0.002 |
| Predicted peak VO2, % | 49 [39, 60] | 52 [43, 62] | 0.074 |
| Predicted Peak VO2 Quartiles | 0.063 | ||
| Top peak VO2 quartile | 37 (21%) | 44 (30%) | |
| 2nd peak VO2 quartile | 46 (26%) | 35 (24%) | |
| 3rd peak VO2 quartile | 41 (23%) | 40 (27%) | |
| Bottom peak VO2 quartile | 53 (30%) | 27 (19%) | |
| Demographic/surgical indices | |||
| Body surface area, m2 | 1.89 [1.74, 2.02] | 1.68 [1.58,1.83] | <0.001 |
| Body mass index, kg/m2 | 24.1 [20.8, 26.6] | 23.8 [21.2,27.3] | 0.322 |
| Systemic left ventricle | 124 (70%) | 102 (70%) | 0.834 |
| Atriopulmonary Fontan | 61 (35%) | 50 (34%) | 0.672 |
| Vital signs | |||
| Systolic blood pressure, mmHg | 111±15 | 109±12 | 0.134 |
| Diastolic blood pressure, mmHg | 68±12 | 68±9 | 0.863 |
| Pulse pressure, mmHg | 44±12 | 41±10 | 0.053 |
| Systemic oxygen saturation, % | 92 (90–95) | 92 (89–94) | 0.624 |
| Comorbidities | |||
| Atrial arrhythmias | |||
| Atrial flutter/tachycardia | 52 (29%) | 48 (33%) | 0.533 |
| Atrial fibrillation | 29 (16%) | 30 (21%) | 0.314 |
| CKD III-V | 11 (6%) | 8 (6%) | 0.834 |
| Cirrhosis | 46 (26%) | 33 (23%) | 0.476 |
| Medications | |||
| Loop diuretics | 73 (41%) | 59 (40%) | 0.933 |
| Beta blockers | 69 (39%) | 59 (40%) | 0.842 |
| Calcium channel blockers | 17 (10%) | 10 (7%) | 0.414 |
| ACEI/ARB | 119 (67%) | 81 (55%) | 0.033 |
| MRA | 43 (34%) | 38 (26%) | 0.724 |
| Laboratory data | |||
| NTproBNP, pg/ml | 205 [82, 459] | 159 [66, 451] | 0.532 |
| GFR, ml/min/1.73 m2 | 97 [76, 112] | 94 [78, 109] | 0.413 |
| Hemoglobin, g/dl | 15.6±2.0 | 14.4±1.9 | <0.001 |
| Echocardiography | |||
| Ventricular ejection fraction | 48 [43,54] | 49 [44, 56] | 0.618 |
| ≥ Mod systemic AVVR | 23 (13%) | 22 (15%) | 0.464 |
| Cardiac MRI | |||
| Ventricular EDVi, ml/m2 | 99±21 | 92±23 | 0.242 |
| Ventricular ESVi, ml/m2 | 53±15 | 49±17 | 0.431 |
| Ventricular SV index, ml/m2 | 47±13 | 43±15 | 0.144 |
| Ventricular ejection fraction | 53±14 | 50±13 | 0.262 |
| Cardiac catheterization | |||
| Fontan pressure, mmHg | 14 [12, 17] | 13 [12, 17] | 0.634 |
| PAWP, mmHg | 10 [7,12] | 9 [7, 11] | 0.683 |
| TPG, mmHg | 4 [2, 6] | 4 [2,6] | 0.874 |
| PVR index, WU*m2 | 1.89 [1.42, 2.61] | 2.01 [1.49, 2.63] | 0.821 |
| Qs index, l/min/m2 | 2.38 [1.88, 2.89] | 2.21 [1.76, 2.55] | 0.062 |
Abbreviations: ACEI/ARB: Angiotensin-converting enzyme inhibitor/aldosterone receptor blocker; AV: Atrioventricular; AVVR: Atrioventricular valve regurgitation; EDVi: End-diastolic volume index; ESVi: End systolic volume index; MRI: Magnetic resonance imaging; MRA: Mineralocorticoid receptor antagonist; NTproBNP: N terminal pro hormone brain natriuretic peptide; PAWP: Pulmonary artery wedge pressure; PVR: Pulmonary vascular resistance; Qs: systemic blood flow; SV: Stroke volume; TPG: Transpulmonary gradient; VO2: Oxygen consumption.
Q1 denotes the top quartile while Q4 denotes the bottom quartile of predicted peak oxygen consumption. P values were derived from unpaired t-test and Wilcoxon rank sum test for continuous variables, as well as Fisher’s exact test and goodness of fit test for categorical variables. Data are presented as mean ± standard deviation and median [lower quartile, upper quartile] for continuous variable with normal versus skewed distribution, respectively, and as count (%) for categorical variables.
Correlates of Aerobic Capacity
Table 5 shows univariable and multivariable linear regression models for the correlates of predicted peak VO2. After multivariable adjustments, the correlates of predicted peak VO2 were body mass index (β±SE −2.61±0.95; 2.61% decrease in predicted peak VO2 per 5 kg/m2 increase in body mass index, p=0.009), systemic saturation (β±SE 3.65±0.85; 3.65% increase in predicted peak VO2 per 5% increase in oxygen saturation, p<0.001), and Fontan pressure (β±SE −1.24±0.22; 1.24% decrease in predicted peak VO2 per 1 mmHg increase in Fontan pressures, p<0.001), (Table 5).
Table 5:
Linear Regression Showing Correlates of Predicted Peak Oxygen Consumption
| Univariable analysis | Multivariable analysis | |||
|---|---|---|---|---|
| β±SE | p | β±SE | p | |
| Age, per 5 years | 0.82±0.74 | 0.321 | ||
| Male sex | 1.39±0.79 | 0.023 | ||
| Age of Fontan operation, per 1 year | 0.08±0.19 | 0.374 | ||
| Atriopulmonary Fontan | −1.56±0.94 | 0.142 | ||
| Systemic left ventricle | 0.41±0.29 | 0.024 | ||
| Fontan fenestration | 0.92±1.10 | 0.421 | ||
| Pacemaker | 1.49±0.97 | 0.134 | ||
| Beta blocker use | 0.49±0.82 | 0.643 | ||
| Body mass index, per 5 kg/m2 | −2.35±1.12 | 0.003 | −2.61±0.95 | 0.009 |
| Vitals and labs | ||||
| Systolic BP, per 10 mmHg | −0.01±0.12 | 0.920 | ||
| Systemic saturation, per 5% | 5.35±1.10 | <0.001 | 3.65±0.85 | <0.001 |
| Heart rate, per 5 beats per minute | −0.59±0.19 | 0.005 | ||
| Hemoglobin, g/dl | 0.15±0.40 | 0.731 | ||
| GFR, per 10 ml/min/1.73m2 | 0.26±0.11 | 0.014 | ||
| Echocardiography | ||||
| Estimated ventricular EF, per 5% | 1.60±0.75 | 0.032 | ||
| ≥ Mod systemic AVVR | 0.24±0.27 | 0.130 | ||
| Cardiac MRI | ||||
| Ventricular EDV index, per 5 ml/m2 | 1.05±0.45 | 0.002 | ||
| Ventricular ESV index, per 5 ml/m2 | 0.10±0.20 | 0.581 | ||
| Ventricular SV index, per 5 ml/m2 | 0.25±0.45 | 0.643 | ||
| Ventricular EF, per 5% | 0.05±0.70 | 0.922 | ||
| Cardiac catheterization | ||||
| Fontan pressure, mmHg | −1.11±0.24 | <0.001 | −1.24±0.22 | <0.001 |
| PAWP, mmHg | −1.08±0.23 | <0.001 | ||
| Transpulmonary gradient, mmHg | 1.10±0.84 | 0.241 | ||
| PVR index, WU*m2 | 0.07±0.37 | 0.824 | ||
| Qs index, l/min/m2 | −0.35±0.31 | 0.133 | ||
Abbreviations: AVVR: Atrioventricular valve regurgitation; BP: Blood pressure; EDV: End-diastolic volume; ESV: End systolic volume; EF: Ejection fraction; GFR: Glomerular filtration rate; LV: Left ventricle; MRI: Magnetic resonance imaging; PAWP: Pulmonary artery wedge pressure; PVR: Pulmonary vascular resistance; Qs: Systemic blood flow; SV: Stroke Volume; SE: Standard error.
Data are presented as β coefficient ± standard error. The correlation between covariates and outcome (predicted peak oxygen consumption) was assessed using univariable linear regression analysis. Covariates with p<0.1 on univariable analyses were used to create a multivariable linear regression model, and the final covariate selection was based on stepwise backwards selection, with a p<0.1 required for a covariate to remain in the model.
Prognostic Implications of Aerobic Capacity
Of the 323 patients, 47 (15%) died and 21 (6.5%) underwent heart transplantation during a median follow-up of 5.1 (2.6–10.6) years, yielding a composite outcome of death/transplant in 63 (20%) patients. The 5- and 10-year cumulative incidence of death/transplant was 14% and 20%, respectively for the overall cohort. Figure 1 shows significant between-group differences in the cumulative incidence of death/transplant across the predicted peak VO2 quartiles. The 10-year cumulative incidence of death/transplant was 7%, 9%, 24%, 37% in top, 2nd, 3rd, and 4th quartiles, respectively.
Figure 1: Relationship between peak oxygen consumption and death/transplant.
(Top) Kaplan Meier curves comparing the cumulative incidence of death/transplant between peak oxygen consumption (pVO2) quartiles. P value was derived from log-rank test and represents comparison across all quartiles.
(Bottom) Forest plot showing events, follow-up in patient years (PY), event rates (per 1,000 patient years), and risk of death/transplant across the different pVO2 quartiles. The adjusted hazard ratios (HR) and 95% confidence intervals (CI) were derived from multivariable Cox regression model. Please see Table 6 for the full univariable and multivariable Cox regression model. The HR represents the incremental risk of death/transplant for progression from one quartile to the next one (higher to lower quartile).
Table 6 shows the univariable and multivariable Cox regression models for the correlates of death/transplant. There was a 47% increase in the risk for death/transplant from a higher predicted peak VO2 quartiles to next lower quartile (adjusted HR 1.47, 95% CI 1.09–2.05, p=0.01) after adjustment for demographic indices, anatomic/surgical indices, comorbidities, and hemodynamic indices (Table 6, Figure 1).
Table 6:
Cox Regression Models for Correlates of Death/transplant
| Univariable analysis | Multivariable analysis | |||
|---|---|---|---|---|
| HR (95%CI) | p | HR (95%CI) | p | |
| Predicted peak VO2 quartiles | 1.92 [1.49, 2.49] | <0.001 | 1.47 [1.09, 2.05] | 0.012 |
| Demographic/anatomic indices | ||||
| Age, per 5 years | 1.31 [1.17, 1.47] | <0.001 | 1.23 [1.05,1.43] | 0.009 |
| Male sex | 1.03 [0.62, 1.70] | 0.776 | ||
| Atriopulmonary Fontan | 1.18 [0.71, 1.96] | 0.543 | ||
| Systemic left ventricle | 0.57 [0.35, 0.94] | 0.032 | ||
| Comorbidities/end-organ function | ||||
| Atrial fibrillation | 2.52 [1.50,4.21 | <0.001 | ||
| GFR, pr 10 ml/min/1.73 m2 | 0.78 [0.59, 0.93] | <0.001 | ||
| Cirrhosis | 1.06 [0.84, 1.39] | 0.431 | ||
| Echocardiographic indices | ||||
| Estimated ventricular EF, per 5% | 0.90 [0.62, 1.47] | 0.540 | ||
| ≥ Moderate AVVR | 1.17 [0.92, 1.98] | 0.413 | ||
| Cardiac catheterization | ||||
| Fontan pressure, mmHg | 1.18 [1.11,1.26 | <0.001 | ||
| PAWP, mmHg | 1.25 [1.18,1.33] | <0.001 | 1.22 [1.14–1.31] | <0.001 |
| Cardiac index, L/min/m2 | 1.06 [0.64,1.91] | 0.321 | ||
| PVR index, WU*m2 | 0.95 [0.73,1.04] | 0.542 | ||
Abbreviations: AVVR: Atrioventricular valve regurgitation; CI: Confidence interval; EF: Ejection fraction; GFR: Glomerular filtration rate; HR: Hazard ratio; PAWP: Pulmonary artery wedge pressure; PVR: Pulmonary vascular resistance; VO2: Oxygen consumption
Data are presented as hazard ratio [95% confidence interval]. The correlation between covariates and outcome (death/transplant) was assessed using univariable Cox regression analysis. Covariates with p<0.1 on univariable analyses were used to create a multivariable Cox regression model, and the final covariate selection was based on stepwise backwards selection, with a p<0.1 required for a covariate to remain in the model. The predicted peak VO2 quartiles were modeled as continuous variables, and the reported HRs represent the incremental risk of progressing from one quartile to the next.
DISCUSSION
In this study, we assessed the aerobic capacity of adults with Fontan palliation based on a cross-sectional analysis of a large cohort of patients that underwent cardiopulmonary exercise test. The main findings are as follows: (1) As expected, the overall cohort had reduced aerobic capacity with 98% of the cohort having predicted peak VO2 ≤80%. (2) The median predicted peak VO2 for the entire cohort was 51%, and ranges of predicted peak VO2 for the top and 2nd quartiles were 63–88%, and 51–62%, respectively. (3) The correlates of higher predicted peak VO2 were smaller body mass index, higher systemic saturation, and lower Fontan pressures. (4) The predicted peak VO2 quartiles were associated with outcomes, as evidenced by a 47% increase in the risk for death/transplant from a higher predicted peak VO2 quartiles to next lower quartile.
Several studies have reported aerobic capacity in patients with Fontan palliation, and consistently, these studies have shown that these patients had a lower aerobic capacity compared to patients with biventricular circulation.8–15,22 This is because aerobic capacity is dependent on cardiac, pulmonary, and skeletal muscle function, and these organ-systems are often impaired in adults with Fontan palliation.8–15,22 The Fontan physiology is unique because of the absence of a subpulmonary ventricle, leading to a dependence on passive (nonpulsatile) pulmonary blood flow to provide systemic ventricular preload.23–26 While this physiology is able to maintain systemic ventricular preload and stroke volume at rest, it may not provide adequate cardiac reserve during exercise.23–26 In the context of exercise in patients with normal biventricular physiology, the subpulmonary ventricle is able to augment pulmonary blood flow, and in turn, augment systemic ventricular preload and stroke volume.27 However, this adaptive mechanism is absent in Fontan physiology.27 As a result, cardiac reserve during exercise is heavily dependent on systemic ventricular diastolic function (relaxation and compliance), pulmonary arterial function (arterial compliance and vascular resistance), and systemic venous pressure (systemic venous tone and volume status).25–27 However, patients with Fontan palliation develop pulmonary arterial dysfunction and systemic ventricular diastolic dysfunction over time, further exacerbating cardiac output reserve impairment.25–27 Furthermore, restrictive lung disease and sarcopenia are common in the Fontan population, leading to pulmonary and peripheral impairment during exercise.13,28 Collectively, these factors contribute to the lower peak VO2 often observed in the adult Fontan population compared to patients with biventricular circulation.8–15,22
A normal aerobic capacity, defined as predicted peak VO2 >80%, is associated with a lower risk of cardiovascular events and mortality, and hence has good negative predictive value across different forms of cardiovascular diseases.1–5 Having a normal aerobic capacity is relatively uncommon in the Fontan population, and such patients often referred to as ‘super Fontan’.8–15,22 Ohuchi et al reviewed exercise test data of 404 adult and pediatric patients with Fontan palliation, and observed that 77 (19%) of the patients had normal aerobic capacity.13 They observed that the proportion of ‘super Fontan’ patients decreased with age, and none of the super Fontan patients was above 25 years of age.13 This is consistent with results from other studies reporting higher prevalence of super Fontan in up to 34% of pediatric patients (average age at exercise test of 12 years), and a lower prevalence of 14% in adult patients (average age at exercise test of 23 years).8,10 In the current study, only 2% of the cohort had normal aerobic capacity, and this may reflect the older age of the cohort (average age at exercise test of 29 years) relative to previous studies.8–15,22 In a previous study, we observed a temporal decrease in predicted peak VO2 by 4 percentage point over a period of 4 years, and the extent of decline in predicted peak VO2 correlated with decrease in systemic ventricular stroke volume index suggesting cardiac reserve impairment as a potential mechanism for the observed decline in aerobic capacity.7 Furthermore, temporal decline in aerobic capacity is more pronounced in patients with lower level of physical activity, suggesting contribution from skeletal muscle impairment as a potential mechanism for observed decline in aerobic capacity.9 Collectively, these factors may explain the low prevalence of super Fontan, and overall lower aerobic capacity (median predicted peak VO2 51%) observed in the current cohort, compared to previous studies.8–15,22
The correlates of higher aerobic capacity in the current study were lower body mass index, higher systemic oxygen saturation, and lower Fontan pressures. A higher systemic saturation and lower Fontan pressures suggest an efficient Fontan circulation (with lower likelihood of pulmonary vascular disease and overt ventricular diastolic dysfunction), which in turn improves cardiac reserve during exercise.24–26 Similar correlates of peak VO2 have reported in previous studies suggesting an intricate relationship between Fontan hemodynamics and aerobic capacity.8,13 An important and consistent finding from previous studies is the relationship between higher level of physical activity and higher peak VO2, as well as an inverse relationship between level of physical activity, and temporal decline in peak VO2.8,10,13,14 While we did not analyze level of physical activity in the current study, we postulate that the relationship between lower body mass index and higher peak VO2 observed in the current study may reflect cardiorespiratory health. This has important clinical application since improvement in level of physical activity is one of the few interventions that has been shown to improve outcomes in patients with Fontan physiology.9,10,22,29
The prognostic implication of aerobic capacity in patients with Fontan physiology has been evaluated in previous studies.30 In a multicenter study of 321 adults with Fontan palliation, Diller et al observed that exercise parameters including predicted peak VO2 were associated with heart failure hospitalization but not the risk of death/transplant.30 In that study, the risk factors for death/transplant included the traditional clinical risk factors such as atrial arrhythmias and atriopulmonary Fontan connection.30 The differences between the results of Diller et al study versus the current study may be due to differences in demographic characteristics. The patients in the current study were older (median age 29 versus 21 years) and had predominance of systemic left ventricle (70% versus 26%), and these factors have been shown to influence clinical outcome in the Fontan population. We observed that separating the cohort into quartiles of predicted peak VO2, demonstrated a trend in prognostic markers of disease severity (cirrhosis, neurohormonal activation, hypoxia, as well as Fontan pressure and wedge pressure) across the quartiles suggesting that aerobic capacity may provide a global assessment of disease severity in this population, and is consistent with the role of aerobic capacity as an important prognostic marker observed in this study.
Clinical Implications and Future Directions
The assessment of the adequacy (lack thereof) of aerobic capacity in adults with Fontan palliation still relies on comparisons with normative values derived from patients with biventricular circulation. However, only a small proportion of older Fontan population (2% of the current cohort) had normal peak VO2, hence limiting the applicability of these criteria in this population. The current study provides estimates of what the expected peak VO2 should be in older Fontan patients, and hence would help calibrate interpretation of exercise test data in adults with Fontan palliation and improve risk stratification in this population. For instance, while peak VO2 of 50–80% would be interpreted as reduced aerobic capacity, it actually represents the top 2 quartiles of aerobic capacity of adult Fontan patients, and such patients had higher transplant-free survival compared to other patients.
Limitations
This is a retrospective single-center cohort study, and it is therefore prone to selection and ascertainment bias. We did not have exercise test data in all the patients. However, the patients with exercise data had similar clinical characteristics as those without exercise data, suggesting a representative sample. Furthermore, the predicted peak VO2 observed in the current study was relatively lower than that of previous studies of adult Fontan patients, and this may reflect the hemodynamic complexity and advanced disease stage often observed in patients receiving care in tertiary centers.
Conclusions
Impaired aerobic capacity was almost universal in this cohort of adults with Fontan palliation. However, while patients with predicted peak VO2 of 50–80% would normally be considered to having impaired aerobic capacity, these patients represented the top 2 peak VO2 quartiles, and had the lowest risk of death/transplant compared to the other patients. The correlates of higher peak VO2 were smaller body mass index, higher systemic saturation, and lower Fontan pressures, underscoring the importance of good Fontan hemodynamics and maintenance of normal body weight. Further studies are required to validate the prognostic performance of the proposed peak VO2 quartiles, and to determine its potential role for the longitudinal monitoring of individual patients.
CLINICAL SUMMARY.
What is new?
Impaired aerobic capacity was almost universal in this cohort of adults with Fontan palliation.
However, while patients with predicted peak VO2 of 50–80% would normally be considered to have impaired aerobic capacity, these patients represented the top 2 peak VO2 quartiles, and had the lowest risk of death/transplant compared to the other patients.
The correlates of higher peak VO2 were smaller body mass index, higher systemic saturation, and lower Fontan pressures, underscoring the importance of good Fontan hemodynamics and maintenance of normal body weight.
What are the clinical implications?
The results of the current study would help calibrate interpretation of exercise test data in adults with Fontan palliation and improve risk stratification in this population.
There is for new strategies to maintain good Fontan hemodynamics and normal body weight in this population.
Funding:
Dr. Egbe is supported by National Heart, Lung, and Blood Institute (NHLBI) grants (R01 HL158517, R01 HL160761, and R01 HL162830). The MACHD Registry is supported by the Al-Bahar Research grant.
Abbreviations:
- CI
Confidence interval
- HR
Hazard ratio
- IQR
Interquartile range
- VO2
Oxygen consumption
Footnotes
Conflict of Interest: none
Disclosures: none
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