Cardiopulmonary Exercise Testing in Repaired Tetralogy of Fallot: Multiparametric Overview and Correlation with Cardiac Magnetic Resonance and Physical Activity Level

Patients with repaired Tetralogy of Fallot (rToF) typically report having preserved subjective exercise tolerance. Chronic pulmonary regurgitation (PR) with varying degrees of right ventricular (RV) dilation as assessed by cardiac magnetic resonance imaging (MRI) is prevalent in rToF and may contribute to clinical compromise. Cardiopulmonary exercise testing (CPET) provides an objective assessment of functional capacity, and the International Physical Activity Questionnaire (IPAQ) can provide additional data on physical activity (PA) achieved. Our aim was to assess the association between CPET values, IPAQ measures, and MRI parameters. All rToF patients who had both an MRI and CPET performed within one year between March 2019 and June 2021 were selected. Clinical data were extracted from electronic records (including demographic, surgical history, New York Heart Association (NYHA) functional class, QRS duration, arrhythmia, MRI parameters, and CPET data). PA level, based on the IPAQ, was assessed at the time of CPET. Eighty-four patients (22.8 ± 8.4 years) showed a reduction in exercise capacity (median peak VO2 30 mL/kg/min (range 25–33); median percent predicted peak VO2 68% (range 61–78)). Peak VO2, correlated with biventricular stroke volumes (RVSV: β = 6.11 (95%CI, 2.38 to 9.85), p = 0.002; LVSV: β = 15.69 (95% CI 10.16 to 21.21), p < 0.0001) and LVEDVi (β = 8.74 (95%CI, 0.66 to 16.83), p = 0.04) on multivariate analysis adjusted for age, gender, and PA level. Other parameters which correlated with stroke volumes included oxygen uptake efficiency slope (OUES) (RVSV: β = 6.88 (95%CI, 1.93 to 11.84), p = 0.008; LVSV: β = 17.86 (95% CI 10.31 to 25.42), p < 0.0001) and peak O2 pulse (RVSV: β = 0.03 (95%CI, 0.01 to 0.05), p = 0.007; LVSV: β = 0.08 (95% CI 0.05 to 0.11), p < 0.0001). On multivariate analysis adjusted for age and gender, PA level correlated significantly with peak VO2/kg (β = 0.02, 95% CI 0.003 to 0.04; p = 0.019). We observed a reduction in objective exercise tolerance in rToF patients. Biventricular stroke volumes and LVEDVi were associated with peak VO2 irrespective of RV size. OUES and peak O2 pulse were also associated with biventricular stroke volumes. While PA level was associated with peak VO2, the incremental value of this parameter should be the focus of future studies.

Predictors of Exercise Capacity in Dilated Cardiomyopathy with Focus on Pulmonary Venous Flow Recorded with Transesophageal Eco-Doppler

The aim of this study was to clarify the relative contribution of elevated left ventricle (LV) filling pressure (FP) estimated by pulmonary venous (PV) and mitral flow, transesophageal Doppler recording (TEE), and other extracardiac factors like obesity and renal insufficiency (KI) to exercise capacity (ExC) evaluated by cardiopulmonary exercise testing (CPX) in patients with dilated cardiomyopathy (DCM). During the CPX test, 119 patients (pts) with DCM underwent both peak VO2 consumption and then TEE with color-guided pulsed-wave Doppler recording of PVF and transmitral flow. In 78 patients (65%), peak VO2 was normal or mildly reduced (>14 mL/kg/min) (group 1) while it was markedly reduced (≤14 mL/kg/min) in 41 (group 2). In univariate analysis, systolic fraction (S Fract), a predictor of elevated pre-a LV diastolic FP, appeared to be the best diastolic parameter predicting a significantly reduced peak VO2. Logistic regression analysis identified five parameters yielding a unique, statistically significant contribution in predicting reduced ExC: creatinine clearance < 52 mL/min (odds ratio (OR) = 7.4, p = 0.007); female gender (OR = 7.1, p = 0.004); BMI > 28 (OR = 5.8, p = 0.029), age > 62 years (OR = 5.5, p = 0.03), S Fract < 59% (OR = 4.9, p = 0.02). Conclusion: KI was the strongest predictor of reduced ExC. The other modifiable factors were obesity and severe LV diastolic dysfunction expressed by blunted systolic venous flow. Contrarily, LV ejection fraction was not predictive, confirming other previous studies. This has important clinical implications.

Performance of Heart Failure Patients with Severely Reduced Ejection Fraction during Cardiopulmonary Exercise Testing on Treadmill and Cycle Ergometer; Similarities and Differences

Background: Peak oxygen consumption (VO2) measured by cardiopulmonary exercise testing (CPET) is a significant predictor of mortality and future transplantation in heart failure patients with severely reduced ejection fraction (HFrEF). The present study evaluated the differences in peak VO2 and other prognostic variables between treadmill and cycle CPETs in these patients. Methods: In this cross-over study design, thirty males with severe HFrEF underwent CPET on both a treadmill and a cycle ergometer within 2–5 days apart, and important CPET parameters between two exercise test modalities were compared. Results: Peak VO2 was 23.12% higher on the treadmill than on cycle (20.55 ± 3.3 vs. 16.69 ± 3.01, p < 0.001, respectively). Minute ventilation to carbon dioxide production (VE/VCO2) slope was not different between the two CPET modes (p = 0.32). There was a strong positive correlation between the VE/VCO2 slopes during treadmill and cycle testing (r = 0.79; p < 0.001). VE/VCO2 slope was not related to peak respiratory exchange ratio (RER) in either modality (treadmill, r = 0.13, p = 0.48; cycle, r = 0.25, p = 0.17). The RER level was significantly higher on the cycle ergometer (p < 0.001). Conclusion: Peak VO2 is higher on treadmill than on cycle ergometer in severe HFrEF patients. In addition, VE/VCO2 slope is not a modality dependent parameter and is not related to the patients’ effort during CPET.

782 Cardiopulmonary exercise testing in patients with COVID-19 at 3 months from hospital discharge

Aims The long-term COVID-19 effects are currently unknown. Whether and for how long symptoms extend beyond the acute phase of the disease is unresolved. Aim of this study was to determine the functional capacity of COVID-19 survivors by cardiopulmonary exercise testing (CPET) and describe its association with dyspnoea, the most frequent symptom after discharge from a tertiary care hospital. Methods and results All COVID-19 patients discharged from our tertiary care institution were enrolled in a prospective follow-up study which would assess clinical, instrumental and laboratory characteristics of COVID-19 survivors at 3 months from hospital discharge (i.e. long-covid). To limit bias in dyspnoea quantification, patients hospitalized in residential care facilities with severe cognitive impairment/disability, ischaemic cardiopathy, and/or heart failure and severe respiratory disease (i.e. chronic obstructive pulmonary disease) were excluded. Clinical evaluation included: peripheral blood samples including inflammatory cytokines, pulmonary function testing (functional respiratory and 6 min-walking test), lung ultrasound, ECG recording, and a comprehensive echocardiographic exam. All patients with peripheral oxygen desaturation at 6 min-walking test (SpO2 &lt; 92%), dyspnoea and with a history of hospitalization in critical care settings were referred for CPET. Dyspnoea was classified with the Medical Research Council (MRC) scale. From June 2020 to May 2021, 198 patients were enrolled; overall, 42% of patients presented with dyspnoea at 3 months from hospital discharge with no difference according to disease severity on hospital admission (P = 0.233). Clinical, laboratory, and echocardiographic parameters were similar between patients with and without dyspnoea. At CPET, 61% of patients complaining dyspnoea showed a %peak VO2 lower than 85% of the predicted value, associated with a lower exercising tolerance and duration and with a globally reduced equivalent metabolic load (METS: 5.3 ± 1.2 vs. 6.6 ± 1.6, P = 0.003). Mean anaerobic threshold was lower for symptomatic patients (46 + 13 vs. 50 + 10, P = 0.03). At multivariable logistic regression analysis, after adjustment for age, number of comorbidities, and body mass index, only %peak VO2 (HR: 0.973; 95% CI: 0.948–0.998) and male gender (HR: 0.548; 95% CI: 0.328–0.999) were associated with dyspnoea. Conclusions At 3-months, almost 1-in-2 patients discharged for COVID-19 pneumonia presented with dyspnoea, irrespective of disease severity. Among patients undergoing CPET, only %peak VO2 and gender were associated with symptoms suggesting a potential systemic inflammatory-mediated response and important gender related differences for the long-covid.

789 Cardiopulmonary exercise testing in repaired tetralogy of Fallot patients: correlation with the level of physical activity and cardiac magnetic resonance imaging

Aims Patients with repaired Tetralogy of Fallot (rToF) tend to have a decent life free of limitations. In asymptomatic individuals, cardiac magnetic resonance imaging (MRI) is used to determine if pulmonary valve replacement (PVR) is necessary. Cardiopulmonary exercise testing (CPET) could aid in determining the extent of functional impairment. Methods and results rToF patients who had an MRI and CPET between 2019 and 2021 in a brief interval (&lt;1 year) were included in the study. Data were gathered on demographics, CPET parameters, MRI, type of surgery, clinical functional class, QRS duration, arrhythmic events, and level of physical activity. A total of 83 participants were enrolled in this study. There was a slight decrease in exercise capacity (median peak VO2/kg 30; range 25–33 mlO2/kg/min). Peak VO2 (r = 0.28), peak VO2/kg (r = 0.40), VO2 at AT (r = 0.31), peak oxygen pulse (r = 0.26), and oxygen uptake efficiency slope (OUES) (r = 0.35) values were found to have a positive association with right ventricular (RV) size. No significant correlation was observed between CPET parameters and PR, LVEF, and RVEF. A significant positive association was detected between right ventricular end-diastolic volume index (RVEDVi) and exercise capacity, especially up to 160 ml/m2. The analysis of the International Physical Activity Questionnaire (IPAQ) replies revealed a statistically significant relationship between the level of physical activity and both peak HR and the indexes of ventilatory efficiency. Conclusion In rToF patients with moderate–severe PR, NYHA class I, preserved RVEF, a slight reduction in exercise tolerance was detected. OUES could also be valuable to this population. A positive association was found between RV dilation and exercise performance up to 160 ml/m2 of RVEDVi, suggesting that perhaps at this cut-off value of RVEDVi, PVR could start being considered.

Aerobic Responses to FES-Assisted and Volitional Cycling in Children with Cerebral Palsy

Recumbent stationary cycling is a potential exercise modality for individuals with cerebral palsy (CP) that lack the postural control needed for upright exercises. Functional electrical stimulation (FES) of lower extremity muscles can help such individuals reach the cycling intensities that are required for aerobic benefits. The aim of this study was to examine the effect of cycling with and without FES assistance to that of a no-intervention control group on the cardiorespiratory fitness of children with CP. Thirty-nine participants were randomized to a FES group that underwent an 8-week FES-assisted cycling program, the volitional group (VOL), who cycled without FES, or a no-intervention control group (CON) (15 FES, 11 VOL, 13 CON). Cadence, peak VO2, and net rise in heart rate were assessed at baseline, end of training, and washout (8-weeks after cessation of training). Latent growth curve modeling was used for analysis. The FES group showed significantly higher cycling cadences than the VOL and CON groups at POST and WO. There were no differences in improvements in the peak VO2 and peak net HR between groups. FES-assisted cycling may help children with CP attain higher cycling cadences and to retain these gains after training cessation. Higher training intensities may be necessary to obtain improvements in peak VO2 and heart rate.

EXPRESS: The association of six minute walk work and other clinical measures to cardiopulmonary exercise test parameters in pulmonary vascular disease

In pulmonary vascular disease (PVD) exercise abnormalities can include reduced exercise capacity, reduced oxygen pulse (O2 pulse) and elevated VE/VCO2. The association of clinical measures such as 6 minute walk work (6MWW), haemodynamics, lung function and echocardiogram to peak VO2, O2 pulse and VE/VCO2 has not been fully investigated in PVD Aims: To determine the relationship of 6MWW and other clinical measures to peak VO2, peak O2 pulse and VE/VCO2. Additionally, to investigate the ability to predict peak VO2 from 6MWW and other clinical parameters. Methods: Clinical data was retrospectively analysed from 63 chronic thromboembolic pulmonary hypertension (CTEPH) and 54 chronic thromboembolic disease (CTED) patients. 6 minute walk test measures, haemodynamics, lung function and echocardiographic measures were correlated with peak VO2, peak O2 pulse and VE/VCO2. Predictive equations were developed to predict peak V̇O2 in both CTEPH and CTED cohorts and subsequently validated. Results: A number of clinical parameters correlated to peak VO2, peak O2 pulse and VE/VCO2. 6MWW and TLCO demonstrated the strongest correlation to peak VO2 and peak O2 pulse. The validation of the predictive equations showed a variable level of agreement between measured peak VO2 and calculated peak VO2 from the predictive equations. Conclusion: 6MWW and additionally a number of clinical test parameters were associated to peak VO2, peak O2 pulse and VE/VCO2. 6MWW and TLCO were particularly highly correlated to peak VO2 and similarly to peak O2 pulse. The validation of the predictive equations showed a variable level of agreement and therefore may have limited clinical applicability.

The Effect of Voxelotor on Exercise Capacity of Youths with Sickle Cell Anemia

Background/Hypothesis: Children and adults with sickle cell anemia (SCA) exhibit decreased cardiopulmonary fitness. Anemia is directly related to oxygen carrying capacity and is one factor that affects cardiopulmonary fitness. The new sickle cell drug voxelotor raises hemoglobin in patients with SCA treated or untreated with hydroxyurea. We hypothesized that voxelotor improves exercise capacity in youths with SCA. Methods: A single-center, open-label, single-arm longitudinal interventional pilot study was conducted for patients with SCA age &gt; 12. Participants performed baseline Cardiopulmonary Exercise Testing (CPET#1), took 1500mg voxelotor for 2 months, then CPET was repeated (CPET#2). A modified Bruce Protocol using 2-minute stages was performed on a motorized treadmill, for a goal of 8-12 minutes of exercise. Breath by breath gas exchange data were collected and analyzed using a VMax Encore 29C metabolic cart. The metabolic test included standard monitoring of heart rate, EKG ST changes, arrhythmias, and O2 saturation. A respiratory quotient &gt;1.1 was used as evidence of participant effort. Peak oxygen consumption (peak VO2), anaerobic threshold (AT), O2 pulse, VE/VCO2 slope, and time exercised in CPET#1 and CPET#2 were compared for each participant. The primary endpoint was peak VO2. Hemoglobin (Hgb), reticulocyte count, and bilirubin were measured before CPET#1 and CPET#2. Pill count was used to monitor medication adherence and left shift of the P50 oxygen dissociation curve was used to document biochemical effect of voxelotor. Patient Global Impression of Change (PGIC) and Clinician Global Impression of Change (CGIC) surveys were collected at the end of the study. Statistical analysis was performed using Student's paired T-test. Results: Nine SCA patients ages 12-20, including 4 males and 5 females, completed the study. All had Hgb SS and were stably maintained on hydroxyurea, which was continued without dose change during the study. After 2 months of voxelotor, all participants demonstrated expected hematologic changes, including mean rise in Hgb +1.3 g/dL (95% C.I.= 0.8, 1.7), mean decrease in reticulocyte count -2.4% (95% C.I.= -4.1, -0.8), and mean decrease in bilirubin -0.4 mg/dL (95% C.I.= -0.8, -0.1). All participants demonstrated voxelotor adherence and leftward shift of p50 (Table 1). Oxygen consumption, measured as percent predicted peak VO2 (ml/kg/min), ranged from 52% to 80% in CPET#1 and from 55% to 71% in CPET#2. The changes in peak VO2 for individual participants ranged from -10% to +10% of predicted peak VO2, with a mean difference of -2.2% (95% CI = -7.1, 2.7), which is insignificant (p=0.3). Using +/- 6% as variability in peak VO2 measurement, 5 participants exhibited no change, 3 participants had decrease in peak VO2 of -7%, -9%, and -10%, while peak VO2 increased by +10% for a single participant, who started to exercise on his own after starting voxelotor. Changes in individuals' anaerobic threshold, O2 pulse, VE/VCO2 slope, and time exercised were not significant and did not correlate with changes in peak VO2. All participants achieved respiratory quotient &gt;1.1, assuring participant effort during CPET (Table 2). On the 7-point PGIC questionnaire evaluating activity limitations, symptoms, emotions, and overall quality of life, 7 out of 9 participants reported positive change, including "a great deal better," "definite," and "moderate" improvements. Two participants reported minimal to no change, and no participants reported worsening. In comparison, clinicians reported "minimal" to "much" improvement on CGIC for all participants. Overall, patient impression of improvement was higher than clinician impression of improvement. Conclusion: This pilot study demonstrated the feasibility of using CPET to evaluate exercise capacity longitudinally in youths with SCA. After addition of voxelotor to hydroxyurea for 2 months, all patients perceived global improvement. Peak VO2 did not change in 8 out of 9 participants and improved for 1 participant who exercised between the 2 CPETs. To increase peak VO2, higher Hgb increase, concurrent regular exercise, and longer exposure to voxelotor may be necessary. This study was funded by Global Blood Therapeutics Figure 1 Figure 1. Disclosures Larkin: Forma Therapeutics, Inc.: Research Funding. Dulman: Pfizer: Other: own stock. Kuypers: Forma Therapeutics, Inc.: Research Funding.

Individualized Assessment of Exercise Capacity in Response to Acute and Long-Term Enzyme Replacement Therapy in Pediatric Pompe Disease

Background: Enzyme replacement therapy (ERT) with alglucosidase alfa improves the prospect of patients with infantile-onset Pompe disease (IOPD). However, a progressive decline has been reported. Objective quantification of the response to ERT when assessing newer strategies is warranted. Methods: This combined retrospective-prospective study assessed the acute and long-term effects of ERT on exercise in IOPD patients. Evaluation included cardiopulmonary exercise testing (CPET), 6-min walking test (6MWT), spirometry, motor function test (GMFM-88) and enzyme blood levels. Results: Thirty-four CPETs (17 pre- and 17 two days-post ERT) over variable follow-up periods were performed in four patients. Two days following ERT, blood enzyme levels increased (median, 1.22 and 10.15 μmol/L/h (p = 0.003)). However, FEV1, FVC and GMFM-88, the median 6MWD and the peak VO2 were unchanged. Long-term evaluations showed stabilization in young patients but progressive deterioration in adolescents. Clinical deterioration was associated with more pronounced deterioration in peak VO2 followed in the decreasing order by 6MWD, FVC and GMFM-88. Conclusions: The peak VO2 and 6MWD might serve as more sensitive markers to assess clinical deterioration. More studies are needed to clarify the sensitivity of the peak VO2 and 6MWT for quantification of individualized response. This may be important when assessing newer strategies and formulations in IOPD.