Phan V; Hershenson J; Caldarera L; Larkin SK; Wheeler K; Cortez AL; Dulman R; Briere N; Lewis A; Kuypers FA;
Yang E;

Pediatric blood & cancer [Pediatr Blood Cancer] 2023 May 29, pp. e30423.
Date of Electronic Publication: 2023 May 29.

Background: Individuals with sickle cell anemia (SCA) exhibit decreased exercise capacity. Anemia limits oxygen-carrying capacity and affects cardiopulmonary fitness. The drug voxelotor raises hemoglobin in SCA. We hypothesized that voxelotor improves exercise capacity in youths with SCA.
Methods: In a single-center, open-label, single-arm, longitudinal interventional pilot study (NCT04581356), SCA patients aged 12 and older, stably maintained on hydroxyurea, were treated with 1500 mg voxelotor daily, and performed cardiopulmonary exercise testing before (CPET#1) and after voxelotor (CPET#2). A modified Bruce Protocol was performed on a motorized treadmill, and breath-by-breath gas exchange data were collected. Peak oxygen consumption (peak VO ₂ ), anaerobic threshold, O ₂ pulse, VE/VCO ₂ slope, and time exercised were compared for each participant. The primary endpoint was change in peak VO ₂ . Hematologic parameters were measured before each CPET. Patient Global Impression of Change (PGIC) and Clinician Global Impression of Change (CGIC) surveys were collected.
Results: Ten hemoglobin SS patients aged 12-24 completed the study. All demonstrated expected hemoglobin rise, with average +1.6 g/dL (p = .003) and P ₅₀ left shift of average -11 mmHg (p < .0001) with decreased oxygen off-loading at low pO ₂ . The change in % predicted peak VO ₂ from CPET#1 to CPET#2 ranged from -12.8% to +11.3%, with significant improvement of more than 5% in one subject, more than 5% decrease in five subjects, and insignificant change of less than 5% in four subjects. All 10 CGIC and seven of 10 PGIC responses were positive.
Conclusion: In a pilot study of 10 youths with SCA, voxelotor treatment did not improve peak VO ₂ in 9 out of 10 patients.

Tobita K; Goda A; Teruya K; Nishida Y; Takeuchi K; Kikuchi H; Inami T; Kohno T; Tashiro S;Yamada S; .Satoh T; Soejima K;

Journal of the American Heart Association [J Am Heart Assoc] 2023 Jun 01, pp. e026890.
Date of Electronic Publication: 2023 Jun 01.

Background The symptom for identification of pulmonary arterial hypertension (PAH) is dyspnea on exertion, with a concomitant decrease in exercise capacity. Even patients with hemodynamically improved PAH may have impaired exercise tolerance; however, the effect of central and peripheral factors on exercise tolerance remains unclear. We explored the factors contributing to exercise capacity and ventilatory efficiency in patients with hemodynamically normalized PAH after medical treatment.
Methods and Results In total, 82 patients with PAH (age: median 46 [interquartile range, 39-51] years; male:female, 23:59) and mean pulmonary arterial pressure ≤30 mm Hg at rest were enrolled. The exercise capacity, indicated by the 6-minute walk distance and peak oxygen consumption, and the ventilatory efficiency, indicated by the minute ventilation versus carbon dioxide output slope, were assessed using cardiopulmonary exercise testing with a right heart catheter. The mean pulmonary arterial pressure was 21 (17-25) mm Hg, and the 6-minute walk distance was 530 (458-565) m, whereas the peak oxygen consumption was 18.8 (14.8-21.6) mLꞏmin ^-1 ꞏkg ^-1 . The multivariate model that best predicted 6-minute walk distance included peak arterial mixed venous oxygen content difference (β=0.46, P <0.001), whereas the best peak oxygen consumption predictors included peak cardiac output (β=0.72, P <0.001), peak arterial mixed venous oxygen content difference (β=0.56, P <0.001), and resting mean pulmonary arterial pressure (β=-0.25, P =0.026). The parameter that best predicted minute ventilation versus carbon dioxide output slope was the resting mean pulmonary arterial pressure (β=0.35, P =0.041). Quadriceps muscle strength was moderately correlated with exercise capacity (6-minute walk distance; ρ=0.57, P <0.001; peak oxygen consumption: ρ=0.56, P <0.001) and weakly correlated with ventilatory efficiency (ρ = -0.32, P =0.007).
Conclusions Central and peripheral factors are closely related to impaired exercise tolerance in patients with hemodynamically normalized PAH.

Bilak JM; Yeo JL; Gulsin GS; Marsh AM; Sian M; Dattani A; Ayton SL; Parke KS; Bain M; Pang W; Boulos S; Pierre TGS; Davies MJ; Yates T; McCann GP; Brady EM;

Journal of cardiovascular development and disease [J Cardiovasc Dev Dis] 2023 Apr 24; Vol. 10 (5).
Date of Electronic Publication: 2023 Apr 24.

Type 2 diabetes (T2D) confers a high risk of heart failure frequently with evidence of cardiovascular structural and functional abnormalities before symptom onset. The effects of remission of T2D on cardiovascular structure and function are unknown. The impact of the remission of T2D, beyond weight loss and glycaemia, on cardiovascular structure and function and exercise capacity is described. Adults with T2D without cardiovascular disease underwent multimodality cardiovascular imaging, cardiopulmonary exercise testing and cardiometabolic profiling. T2D remission cases (Glycated hemoglobin (HbA1c) < 6.5% without glucose-lowering therapy, ≥3 months) were propensity score matched 1:4 based on age, sex, ethnicity and time of exposure to those with active T2D ( n = 100) with the nearest-neighbour method and 1:1 with non-T2D controls ( n = 25). T2D remission was associated with a lower leptin-adiponectin ratio, hepatic steatosis and triglycerides, a trend towards greater exercise capacity and significantly lower minute ventilation/carbon dioxide production (VE/VCO2 slope) vs. active T2D (27.74 ± 3.95 vs. 30.52 ± 5.46, p < 0.0025). Evidence of concentric remodeling remained in T2D remission vs. controls (left ventricular mass/volume ratio 0.88 ± 0.10 vs. 0.80 ± 0.10, p < 0.025). T2D remission is associated with an improved metabolic risk profile and ventilatory response to exercise without concomitant improvements in cardiovascular structure or function. There is a requirement for continued attention to risk factor control for this important patient population.

Pernot J; Ribon A; Degano B;

Respiratory medicine and research [Respir Med Res] 2023 Apr 29; Vol. 83, pp. 101022.
Date of Electronic Publication: 2023 Apr 29.

Background: The identification of the first ventilatory threshold (VT1) on an incremental cardiopulmonary exercise test (CPET) is useful to guide exercise reconditioning. However, determination of the VT1 is sometimes difficult in patients with chronic respiratory disease. Our hypothesis was that it would be possible to identify a “clinical threshold” based on patients’ perceptions at which they subjectively consider that they can perform endurance training during a rehabilitation programme.
Methods: Workloads at which patients identified a “clinical threshold” during a submaximal exercise were compared with workloads recorded at VT1 determined during a maximal CPET. Patients with a VT1 and/or a “clinical threshold” obtained at a workload <25 W were excluded from the analysis.
Results: A “clinical threshold” could be determined in the 86 patients included. Data from 63 patients were retained for the analysis, of which only 52 had a VT1 that could be identified. The agreement between the workloads determined at VT1 and at the “clinical threshold” was almost perfect, with a Lin’s concordance coefficient (cc) of 0.82.
Conclusions: In the context of chronic respiratory diseases, it is possible to use patients’ sensations (which are by nature subjective) to identify a workload on a cycle ergometer, which corresponds to the workload at the first ventilatory threshold determined objectively during CPET.
Competing Interests: Declaration of Competing Interest Prof. Degano reports personal fees and non-financial support from GSK, Chiesi, AstraZeneca, Nuvaira, Menarini and Boehringer Ingelheim, outside the submitted work. The other authors declare that they have no conflict of interest for the submitted work. The results of the present study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation.

Schierbauer J; Wolf A; Wachsmuth NB; Maassen N; Schmidt WFJ;

Metabolites [Metabolites] 2023 May 06; Vol. 13 (5).
Date of Electronic Publication: 2023 May 06.

We wanted to determine the influence of total blood volume (BV) and blood lactate quantity on lactate concentrations during incremental exercise. Twenty-six healthy, nonsmoking, heterogeneously trained females (27.5 ± 5.9 ys) performed an incremental cardiopulmonary exercise test on a cycle ergometer during which maximum oxygen uptake (V·O _2max ), lactate concentrations ([La ^– ]) and hemoglobin concentrations ([Hb]) were determined. Hemoglobin mass and blood volume (BV) were determined using an optimised carbon monoxide-rebreathing method. V·O _2max and maximum power (P _max ) ranged between 32 and 62 mL·min ^-1 ·kg ^-1 and 2.3 and 5.5 W·kg ^-1 , respectively. BV ranged between 81 and 121 mL·kg ^-1 of lean body mass and decreased by 280 ± 115 mL (5.7%, p = 0.001) until P _max . At P _max , the [La ^– ] was significantly correlated to the systemic lactate quantity (La ^– , r = 0.84, p < 0.0001) but also significantly negatively correlated to the BV (r = -0.44, p < 0.05). We calculated that the exercise-induced BV shifts significantly reduced the lactate transport capacity by 10.8% ( p < 0.0001). Our results demonstrate that both the total BV and La ^– have a major influence on the resulting [La ^– ] during dynamic exercise. Moreover, the blood La ^– transport capacity might be significantly reduced by the shift in plasma volume. We conclude, that the total BV might be another relevant factor in the interpretation of [La ^– ] during a cardio-pulmonary exercise test.

Kroesen SH; Bakker EA;Snoek JA; van Kimmenade RRJ; Molinger J; Araújo CG; Hopman MTE; Eijsvogels TMH;

Medicine and science in sports and exercise [Med Sci Sports Exerc] 2023 May 15.
Date of Electronic Publication: 2023 May 15.

Introduction: We assessed the cardiorespiratory optimal point (COP) – the minimal VE/VO2 in a given minute of an incremental cardiopulmonary exercise test – in patients with heart failure (HF) and aimed to determine 1) its association with patient and disease characteristics, 2) changes following an exercise-based cardiac rehabilitation program (CR), and 3) the association with clinical outcomes.
Methods: We studied 277 HF patients (67 [58-74] years, 30% female, 72% HFrEF) between 2009 and 2018. Patients participated in a 12- to 24-week CR program, and COP was assessed pre- and post-CR. Patient and disease characteristics and clinical outcomes (mortality and cardiovascular-related hospitalization) were extracted from patient files. The incidence of clinical outcomes was compared across COP tertiles (low: <26.0; moderate: 26.0-30.7; high: >30.7).
Results: Median COP was 28.2 [24.9-32.1] and was reached at 51 ± 15% of VO2peak. Lower age, female sex, higher body mass index, the absence of a pacemaker or the absence of chronic obstructive pulmonary disease and lower NT-proBNP concentrations were associated with a lower COP. Participation in CR reduced COP (-0.8, 95% confidence interval (CI): -1.3; -0.3). Low COP had a reduced risk (adjusted hazard ratio 0.53, 95%CI 0.33; 0.84) for adverse clinical outcomes as compared to high COP.
Conclusions: Classic cardiovascular risk factors are associated with a higher, more unfavorable, COP. CR-based exercise training reduces COP, while a lower COP is associated with a better clinical prognosis. As COP can be established during a submaximal exercise test, this may offer novel risk stratification possibilities for HF care programs.
Competing Interests: Conflict of Interest and Funding Source: This project is supported by a Eurostars Grant (E!114585). All the authors have no conflicts of interest or financial ties to disclose. The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. The results of the present study do not constitute endorsement by the American College of Sports Medicine.

Bryde R; Martinez MW; Emery MS;

Progress in cardiovascular diseases [Prog Cardiovasc Dis] 2023 May 16.
Date of Electronic Publication: 2023 May 16.

Individuals with hypertrophic cardiomyopathy (HCM) have historically been advised to limit exercise and sports participation to mild-intensity activities due to concerns for sudden cardiac arrest (SCA). However, more contemporary data have shown SCA is rare in patients with HCM and emerging data is shifting towards support for the safety of exercise in this patient population. Recent guidelines endorse exercise in patients with HCM after a comprehensive evaluation and shared-decision making with an expert provider.

Competing Interests: Declaration of Competing Interest Dr. Emery reports personal fees (Advisory Board, Speakers Bureau) from Bristol Meyers Squibb. Dr. Martinez reports compensation for his role with Major League Soccer and from the Bristol Meyers Squibb advisory board. Dr. Bryde has no conflicts to report.

Hedge ET; Amelard R; Hughson RL;

Journal of applied physiology (Bethesda, Md. : 1985) [J Appl Physiol (1985)] 2023 May 18.
Date of Electronic Publication: 2023 May 18.

Non-intrusive estimation of oxygen uptake (V̇O ₂ ) is possible with wearable sensor technology and artificial intelligence. V̇O ₂ kinetics have been accurately predicted during moderate exercise using easy-to-obtain sensor inputs. However, V̇O ₂ prediction algorithms for higher intensity exercise with inherent nonlinearities are still being refined. The purpose of this investigation was to test if a machine learning model can accurately predict dynamic V̇O ₂ across exercise intensities, including slower V̇O ₂ kinetics normally observed during heavy- compared to moderate-intensity exercise. Fifteen young healthy adults (7 females; peak V̇O ₂ : 42±5 mL·min ^-1 ·kg ^-1 ) performed three different pseudorandom binary sequence (PRBS) exercise tests ranging in intensity from low-to-moderate, low-to-heavy, and ventilatory threshold-to-heavy work rates. A temporal convolutional network was trained to predict instantaneous V̇O ₂ , with model inputs including heart rate, percent heart rate reserve, estimated minute ventilation, breathing frequency, and work rate. Frequency domain analyses between V̇O ₂ and work rate were used to evaluate measured and predicted V̇O ₂ kinetics. Predicted V̇O ₂ had low bias (-0.017 L·min ^-1 , 95% limits of agreement: [-0.289, 0.254]), and was very strongly correlated ( r _rm =0.974, p <0.001) with the measured V̇O ₂ . The extracted indicator of kinetics, mean normalized gain (MNG), was not different between predicted and measured V̇O ₂ responses (main effect: p =0.374, η _p ² =0.01), and decreased with increasing exercise intensity (main effect: p <0.001, η _p ² =0.64). Predicted and measured V̇O ₂ kinetics indicators were moderately correlated across repeated measurements (MNG: r _rm =0.680, p <0.001). Therefore, the temporal convolutional network accurately predicted slower V̇O ₂ kinetics with increasing exercise intensity, enabling non-intrusive monitoring of cardiorespiratory dynamics across moderate- and heavy-exercise intensities.

Dun Y; Wu S; Cui N; Thomas RJ; Squires RW; Olson TP; Sylvester KP; Fu S; Zhang C; Gao Y; Du Y; Changsha, Xu N; Liu S;

nternational journal of surgery (London, England) [Int J Surg] 2023 May 19.
Date of Electronic Publication: 2023 May 19.

Background: The role of minute ventilation/carbon dioxide production (/CO2) slope, a ventilation efficiency marker, in predicting short- and long-term health outcomes for patients with non-small-cell lung cancer (NSCLC) undergoing lung resection has not been well investigated.
Material and Methods: This prospective cohort study consecutively enrolled NSCLC patients who underwent a presurgical cardiopulmonary exercise test from November 2014 to December 2019. The association of /CO2 slope with relapse-free survival (RFS), overall survival (OS), and perioperative mortality was evaluated using the Cox proportional hazards and logistic models. Covariates were adjusted using propensity score overlap weighting. The optimal cut-off point of the E/CO2 slope was estimated using the Receiver Operating Characteristics curve. Internal validation was completed through bootstrap resampling.
Results: A cohort of 895 patients (median age [interquartile range], 59 [13] years; 62.5% male) was followed for a median of 40 (range, 1-85) months. Throughout the study there were 247 relapses or deaths and 156 perioperative complications. The incidence rates per 1000 person-years for relapses or deaths were 108.8 and 79.6 among patients with high and low E/CO2 slope, respectively (weighted incidence rate difference per 1000 person-years, 29.21 [95% CI, 7.30 to 51.12]). A E/CO2 slope of ≥31 was associated with shorter RFS (hazard ratio for relapse or death, 1.38 [95% CI, 1.02 to 1.88], P=0.04) and poorer OS (hazard ratio for death, 1.69 [1.15 to 2.48], P=0.02) compared to a lower /CO2 slope. A high E/CO2 slope increased the risk of perioperative morbidity compared with a low E/CO2 slope (odds ratio, 2.32 [1.54 to 3.49], P<0.001).
Conclusions: In patients with operable NSCLC, a high E/CO2 slope was significantly associated with elevated risks of poorer RFS and OS, and perioperative morbidity.

Ohuchi H; Mori A; Kurosaki K; Shiraishi I; Nakai M;

American heart journal [Am Heart J] 2023 May 19.
Date of Electronic Publication: 2023 May 19.

Background: Super-Fontan (SF) is an excellent phenotype of patients with Fontan circulation and normal exercise capacity. This study aimed to clarify the prevalence and clinical correlates and characteristics of SF.
Methods: We reviewed 404 Fontan patients who had undergone cardiopulmonary exercise testing, and the results were compared with clinical profiles.
Results: Seventy-seven (19%) patients had SF, and the post-operative prevalence at 5, 10, 15, 20, and ≥ 25 years was 16 (35%), 30 (39%), 18 (19%), 13 (14%), and 0 (0%), respectively. Compared with non-SF, SF patients were younger (p < 0.001) and were mostly men (p < 0.05). SF was characterized by a current high arterial blood pressure and oxygen saturation (SaO ₂ ), low systemic ventricle (SV) end-diastolic pressure, favorable body composition, superior pulmonary function, preserved hepatorenal and hemostatic functions, and better glucose tolerance (p < 0.05-0.001). Pre-Fontan better SV function, low pulmonary artery resistance, and high SaO ₂ were associated with current SF (p < 0.05-0.01). Furthermore, positive trajectory of exercise capacity and high daily activity during childhood were associated with current adult SF (p < 0.05). During the follow-up, 25 patients died, and 74 patients were unexpectedly hospitalized. There was no death in the SF group, and the rate of hospitalization was 67% lower than that of the non-SF group (p < 0.01-0.001).
Conclusions: The prevalence of SF gradually decreased over time. SF was characterized by preserved multi-end-organ function and an excellent prognosis. Pre-Fontan hemodynamics and post-Fontan childhood daily activity were associated with being adult SF.