Tomlinson OW; Barker AR; Fulford J; Wilson P; Shelley J; Oades PJ; Williams CA

Frontiers in pediatrics [Front Pediatr] 2023 Jun 14; Vol. 11, pp. 1211547.
Date of Electronic Publication: 2023 Jun 14 (Print Publication: 2023).

Background: Increased maximal oxygen uptake (V̇O _2max ) is beneficial in children with cystic fibrosis (CF) but remains lower compared to healthy peers. Intrinsic metabolic deficiencies within skeletal muscle (muscle “quality”) and skeletal muscle size (muscle “quantity”) are both proposed as potential causes for the lower V̇O _2max , although exact mechanisms remain unknown. This study utilises gold-standard methodologies to control for the residual effects of muscle size from V̇O _2max to address this “quality” vs. “quantity” debate.
Methods: Fourteen children (7 CF vs. 7 age- and sex-matched controls) were recruited. Parameters of muscle size – muscle cross-sectional area (mCSA) and thigh muscle volume (TMV) were derived from magnetic resonance imaging, and V̇O _2max obtained via cardiopulmonary exercise testing. Allometric scaling removed residual effects of muscle size, and independent samples t -tests and effect sizes (ES) identified differences between groups in V̇O _2max , once mCSA and TMV were controlled for.
Results: V̇O _2max was shown to be lower in the CF group, relative to controls, with large ES being identified when allometrically scaled to mCSA (ES = 1.76) and TMV (ES = 0.92). Reduced peak work rate was also identified in the CF group when allometrically controlled for mCSA (ES = 1.18) and TMV (ES = 0.45).
Conclusions: A lower V̇O _2max was still observed in children with CF after allometrically scaling for muscle size, suggesting reduced muscle “quality” in CF (as muscle “quantity” is fully controlled for). This observation likely reflects intrinsic metabolic defects within CF skeletal muscle.

Althunayyan A; Alborikan S; Badiani S; Wong K; Uppal R; CPatel N; Petersen SE; Lloyd G; Bhattacharyya S;

The American journal of cardiology [Am J Cardiol] 2023 Jun 20; Vol. 201, pp. 8-15.
Date of Electronic Publication: 2023 Jun 20.

The current guidelines recommend intervention in severe degenerative mitral regurgitation (MR) in symptomatic patients or asymptomatic patients with left ventricular dilatation or dysfunction. The insidious onset of symptoms may mean that patients do not report their symptoms. The role of systematic exercise testing for symptoms in MR is not clearly defined. A total of 97 patients with moderate to severe asymptomatic MR underwent exercise echocardiography combined with cardiopulmonary exercise testing. The predictors of exercise-induced dyspnea, symptom-free survival, and mitral valve intervention were identified. A total of 18 patients (19%) developed limiting dyspnea on exercise. Spontaneous symptom-free survival at 24 months was significantly higher in those without exercise-induced symptoms than those with exercise-induced symptoms, p <0.0001. The only independent predictors of spontaneous symptoms at 2 years were effective regurgitant orifice area (odds ratio 27.45, 95% confidence interval [CI] 1.43 to 528.40, p = 0.03) and exercise-induced symptoms (odds ratio 11.56, 95% CI 1.71 to 78.09, p = 0.01). The only independent predictor of surgery was indexed left ventricular systolic volumes (odds ratio 1.17, 95% CI 1.04 to 1.30, p = 0.006). Where only the patients who underwent surgery due to symptoms were included, the only independent predictor was exercise-induced symptoms (odds ratio 13.94, 95% CI 1.39 to 140.27, p = 0.025). In conclusion, in patients with primary asymptomatic degenerative MR, 1/5 develop revealed symptoms during exercise. This predicts a subsequent development of spontaneous symptoms and mitral valve intervention due to symptoms.
Competing Interests: Declaration of Competing Interest Dr. Petersen reports a relation with Circle Cardiovascular Imaging Inc., Calgary, Alberta, Canada (SEP) that includes consulting or advisory. The remaining authors have no conflicts of interest to declare.

Batten K; Bhattacharya K; Simar D; Broderick C;

Journal of inherited metabolic disease [J Inherit Metab Dis] 2023 Jun 22.
Date of Electronic Publication: 2023 Jun 22.

Skeletal muscle is a dynamic organ requiring tight regulation of energy metabolism in order to provide bursts of energy for effective function. Several inborn errors of muscle energy metabolism (IEMEM) affect skeletal muscle function and therefore the ability to initiate and sustain physical activity. Exercise testing can be valuable in supporting diagnosis, however its use remains limited due to the inconsistency in data to inform its application in IEMEM populations. While exercise testing is often used in adults with IEMEM, its use in children is far more limited. Once a physiological limitation has been identified and the aetiology defined, habitual exercise can assist with improving functional capacity, with reports supporting favourable adaptations in adult patients with IEMEM. Despite the potential benefits of structured exercise programs, data in paediatric populations remain limited. This review will focus on the utilisation and limitations of exercise testing and prescription for both adults and children, in the management of McArdle Disease, long chain fatty acid oxidation disorders, and myopathic mitochondrial respiratory chain disorders.

Goulart CDL; Silva RN; Agostoni P; Franssen FME; Myers J; Arena R; Borghi-Silva A;

Respiratory medicine [Respir Med] 2023 Jun 23, pp. 107332.
Date of Electronic Publication: 2023 Jun 23.

Background: Exercise oscillatory ventilation (EOV) is considered an important variable for predicting poor prognosis in patients with heart failure (HF) with reduced left ventricular ejection fraction (HFrEF). However, there are no studies evaluating EOV presence in the coexistence chronic obstructive pulmonary disease (COPD) and HFrEF.
Aims: I) To compare the clinical characteristics of participants with coexisting HFrEF-COPD with and without EOV during cardiopulmonary exercise testing (CPET); and II) to identify the impact of EOV on mortality during follow-up for 35 months.
Methods: 50 stable HFrEF-COPD (EF<50%) participants underwent CPET and were followed for 35 months. The parametric Student’s t-test, chi-square tests, linear regression model and Kaplan-Meier analysis were applied.
Results: We identified 13 (26%) participants with EOV and 37 (74%) without EOV (N-EOV) during exercise. The EOV group had worse cardiac function (LVEF: 30 ± 6% vs. N-EOV 40 ± 9%, p = 0.007), worse pulmonary function (FEV ₁ : 1.04 ± 0.7 L vs. N-EOV 1.88 ± 0.7 L, p = 0.007), a higher mortality rate [7 (54%) vs. N-EOV 8 (27%), p = 0.02], higher minute ventilation/carbon dioxide production (V̇˙ _E / V̇˙ CO ₂ ) slope (42 ± 7 vs. N-EOV 36 ± 8, p = 0.04), reduced peak ventilation (L/min) (26.2 ± 16.7 vs. N-EOV 40.3 ± 16.4, p = 0.01) and peak oxygen uptake (mlO ₂ kg ^-1 min ^-1 ) (11.0 ± 4.0 vs. N-EOV 13.5 ± 3.4 ml●kg ^-1 ●min ^-1 , p = 0.04) when compared with N-EOV group. We found that EOV group had a higher risk of mortality during follow-up (long-rank p = 0.001) than patients with N-EOV group.
Conclusion: The presence of EOV is associated with greater severity of coexisting HFrEF and COPD and a reduced prognosis. Assessment of EOV in participants with coexisting HFrEF-COPD, as a biomarker for both clinical status and prognosis may therefore be warranted.

Zacca R; Castro FAS; Monteiro ASM; Pyne DB; Vilas-Boas JP; Fernandes RJP;

International journal of sports physiology and performance [Int J Sports Physiol Perform] 2023 Jun 23, pp. 1-9.
Date of Electronic Publication: 2023 Jun 23.

Purpose: To compare ventilatory and cardiorespiratory responses between the COSMED AquaTrainer coupled with the K4b2 and K5 wearable metabolic systems in breath-by-breath mode over a wide range of swimming speeds.
Methods: Seventeen well-trained master swimmers performed 2 front-crawl 7 × 200-m incremental intermittent protocols (increments of 0.05 m·s-1 and 30-s rest intervals, with a visual pacer) with AquaTrainer coupled with either K4b2 or K5.
Results: Post hoc tests showed that swimming speed was similar (mean diff.: -0.01 to 0.01 m·s-1; P = .73-.97), repeatable (intraclass correlation coefficient: .88-.99; P < .001), highly accurate, and precise (agreement; bias: -0.01 to 0.01 m·s-1; limits: -0.1 to 0.1 m·s-1) between all conditions. Ventilatory and cardiorespiratory responses were highly comparable between all conditions, despite a “small” effect size for fraction of expired carbon dioxide at the sixth 200-m step (0.5%; ηp2=.12; P = .04) and carbon dioxide production at the fifth, sixth, and seventh 200-m steps (0.3-0.5 L·min-1; ηp2=.11-.17; P = .01-.05). We also observed high accuracy, which was greater for tidal volume (0.0-0.1 L), minute ventilation (-3.7 to 5.1 L·min-1), respiratory frequency (bias: -2.1 to 1.9 beats·min-1), and oxygen uptake (0.0-0.2 L·min-1). Bland-Altman plots showed that the distribution inside the limits of agreement and their respective 95% CIs were consistent for all ventilatory and cardiorespiratory data. The repeatability (intraclass correlation coefficient) of tidal volume (.93-.97), minute ventilation (.82-.97), respiratory frequency (.68-.96), fraction of expired carbon dioxide (.85-.95), carbon dioxide production (.77-.95), fraction of expired oxygen (.78-.92), and oxygen uptake (.94-.98) data ranged from moderate to excellent (P < .001-.05).
Conclusions: Swimming with the AquaTrainer coupled with K5 (breath-by-breath mode) yields accurate, precise, and repeatable ventilatory and cardiorespiratory responses when compared with K4b2 (previous gold standard). Swimming support staff, exercise and health professionals, and researchers can now relate differences between physiological capacities measured with the AquaTrainer while coupled with either of these 2 devices.

Caruso FR; Goulart CDL;Jr JCB; de Oliveira CR; Mendes RG; Arena R; Borghi-Silva A;

Heart & lung : the journal of critical care [Heart Lung] 2023 Jun 24; Vol. 62, pp. 95-100.
Date of Electronic Publication: 2023 Jun 24.

Background: Weber classification stratifies cardiac patients based on peak oxygen consumption (V̇O ₂ ), the gold-standard measure of exercise capacity.
Objective: To determine if Weber classification is a useful tool to discriminate clinical phenotypes in COPD patients and to evaluate if disease severity and other clinical measures can predict V̇O _2peak .
Methods: Three hundred and six COPD patients underwent cardiopulmonary exercise testing (CPX) and were divided according to Weber class: 1) Weber A (n = 34); 2) Weber B (n = 88); 3) Weber C (n = 138); and 4) Weber D (n = 46).
Results: Weber class D patients demonstrated a reduced V̇O _{2 peak} , heart rate (HR), minute ventilation (V̇ _E ) _, oxygen (O ₂ ) pulse, circulatory power (CP), oxygen uptake efficiency slope (OUES), oxygen saturation (SpO ₂ %), delta (Δ)HR and ΔSpO ₂ when compared to Weber A and B (p<0.05). Moreover, Dyspnea and the V̇ _E /carbon dioxide production (V̇CO ₂ ) slope were higher in Weber D compared with Weber C and A (p<0.001). Hierarchical regression analysis demonstrated significant predictors of V̇O _2peak (R ² = 0.131; Adj R ²  = 1.25), including HR (β=0.5757; t = 5.7; P<0.001) and forced expiratory volume in one second (FEV ₁ ) (β=0.119; t = 2.16; P<0.03). Among the Weber C + D groups, predictors of V̇O _2peak (R = 0.78; R ² = 0.60; Adj R ² =0.59), dyspnea (β=0.076; t = 1.111; P<0.27) and maximal voluntary ventilation (MVV) (β=0.75; t = 1.14; P<0.00).
Conclusion: Weber classification may be a useful tool to stratify cardiorespiratory fitness in COPD patients. Other clinical measures may be useful in predicting peak V̇O ₂ in mild-to-severe COPD, moreover different phenotypes may be important tool to improve physical capacity of chronic disease patients.

Mapelli M; Mattavelli I; Paolillo S; Salvioni E; Magrì D; Galotta A; De Martino F; Mantegazza V; Vignati C; Esposito I; Dell’Aversana S; Paolillo R; Capovilla T; Tamborini G; Nepitella AA; Filardi PP; Agostoni P

European journal of clinical pharmacology [Eur J Clin Pharmacol] 2023 Jun 27.
Date of Electronic Publication: 2023 Jun 27.

Purpose: Sacubitril/valsartan is a mainstay of the treatment of heart failure with reduced ejection fraction (HFrEF); however, its effects on exercise performance yielded conflicting results. Aim of our study was to evaluate the impact of sacubitril/valsartan on exercise parameters and echocardiographic and biomarker changes at different drug doses.
Methods: We prospectively enrolled consecutive HFrEF outpatients eligible to start sacubitril/valsartan. Patients underwent clinical assessment, cardiopulmonary exercise test (CPET), blood sampling, echocardiography, and completed the Kansas City Cardiomyopathy Questionnaire (KCCQ-12). Sacubitril/valsartan was introduced at 24/26 mg b.i.d. dose and progressively uptitrated in a standard monthly-based fashion to 97/103 mg b.i.d. or maximum tolerated dose. Study procedures were repeated at each titration visit and 6 months after reaching the maximum tolerated dose.
Results: Ninety-six patients completed the study, 73 (75%) reached maximum sacubitril/valsartan dose. We observed a significant improvement in functional capacity across all study steps: oxygen intake increased, at peak exercise (from 15.6 ± 4.5 to 16.5 ± 4.9 mL/min/kg; p trend = 0.001), while minute ventilation/carbon dioxide production relationship reduced in patients with an abnormal value at baseline. Sacubitril/valsartan induced positive left ventricle reverse remodeling (EF from 31 ± 5 to 37 ± 8%; p trend < 0.001), while NT-proBNP reduced from 1179 [610-2757] to 780 [372-1344] pg/ml (p trend < 0.0001). NYHA functional class and the subjective perception of limitation in daily life at KCCQ-12 significantly improved. The Metabolic Exercise Cardiac Kidney Index (MECKI) score progressively improved from 4.35 [2.42-7.71] to 2.35% [1.24-4.96], p = 0.003.
Conclusions: A holistic and progressive HF improvement was observed with sacubitril/valsartan in parallel with quality of life. Likewise, a prognostic enhancement was observed.

Dierckx W; De Backer W; Ides K; De Meyer Y; Lauwers E; Franck E;

Physiological reports [Physiol Rep] 2023 Jun; Vol. 11 (12), pp. e15754.

Patients with post-acute sequelae of COVID-19 (PASC) present with a decrease in physical fitness. The aim of this paper is to reveal the relations between the remaining symptoms, blood volume distribution, exercise tolerance, static and dynamic lung volumes, and overall functioning. Patients with PASC were retrospectively studied. Pulmonary function tests (PFT), 6-minute walk test (6MWT), and cardiopulmonary exercise test were performed. Chest CT was taken and quantified. Patients were divided into two groups: minor functional limitations (MFL) and severe functional limitations (SFL) based on the completed Post-COVID-19 Functional Status scale (PCFS). Twenty one patients (3 M; 18 FM), mean age 44 (IQR 21) were studied. Eighteen completed the PCFS (8 MFL; 10 SFL). VO ₂ max was suboptimal in both groups (not significant). 6MWT was significantly higher in MFL-group (p = 0.043). Subjects with SFL, had significant lower TLC (p = 0.029). The MFL-group had more air trapping (p = 0.036). Throughout the sample, air trapping correlated significantly with residual volume (RV) in L (p < 0.001). An increase in air trapping was related to an increase in BV5 (p < 0.001). Mean BV5 was 65% (IQR 5%). BV5% in patients with PASC was higher than in patients with acute COVID-19 infection. This increase in BV5% in patients with PASC is thought to be driven by the air trapping in the lobes. This study reveals that symptoms are more driven by occlusion of the small airways. Patients with more physical complaints have significantly lower TLC. All subjects encounter physical limitations as indicated by suboptimal VO ₂ max. Treatment should focus on opening or re-opening of small airways by recruiting alveoli.

Gama F; Rocha B; Aguiar C; Strong C; Freitas P; Brízido C; Tralhão A; Durazzo A; Mendes M;

Heart, lung & circulation [Heart Lung Circ] 2023 Jun 15.
Date of Electronic Publication: 2023 Jun 15.

Background: Several heart failure (HF) prognostic risk scores are available to guide the ideal time for listing candidates for a heart transplant (HTx). The detection of exercise oscillatory ventilation (EOV) during cardiopulmonary exercise testing (CPET) is associated with advanced HF and a worse prognosis, and yet it is not accounted for in these risk scores. Therefore, this study aimed to assess whether EOV further adds prognostic value to HF scores.
Methods: A single-centre retrospective cohort study was undertaken of consecutive HF patients with reduced ejection fraction (HFrEF) who underwent CPET from 1996 to 2018. The Heart Failure Survival Score (HFSS), Seattle Heart Failure Model (SHFM), Meta-analysis Global Group In Chronic Heart Failure (MAGGIC), and Metabolic Exercise Cardiac Kidney Index (MECKI) were calculated. The added value of EOV on top of those scores was assessed using a Cox proportional hazard model. The added discriminative power was also assessed by receiver operating characteristic curve comparison.
Results: A total of 390 HF patients with a median age of 58 (IQR 50-65) years were investigated, of whom 78% were male and 54% had ischaemic heart disease. The median peak oxygen consumption was 15.7 mL/kg/min (IQR 12.8-20.1). Exercise oscillatory ventilation was detected in 153 (39.2%) patients. Over a median follow-up of 2 years, 61 patients died (49 due to a cardiovascular reason) and 54 had a HTx. Exercise oscillatory ventilation independently predicted the composite outcome of all-cause death and HTx. Furthermore, the presence of this ventilatory pattern significantly improved the prognostic performance of both HFSS and MAGGIC scores.
Conclusion: Exercise oscillatory ventilation was often found in a cohort of HF patients with reduced LVEF who underwent CPET. It was found that EOV added further prognostic value to contemporary HF scores, suggesting that this easily obtained parameter should be included in future modified HF scores.

O’Shea O; Casey S;Giblin C; Stephenson A; Carroll TP; McElvaney NG; McDonough SM;

International journal of chronic obstructive pulmonary disease [Int J Chron Obstruct Pulmon Dis] 2023 Jun 16; Vol. 18, pp. 1231-1250.
Date of Electronic Publication: 2023 Jun 16 (Print Publication: 2023).

Alpha-1 antitrypsin deficiency (AATD) is a hereditary disorder and a genetic risk factor for chronic obstructive pulmonary disease (COPD). Physical activity (PA) is important for the prevention and treatment of chronic disease. Little is known about PA in people with AATD. Therefore, we aimed to map the research undertaken to improve and/or measure PA, sedentary behaviour (SB) or exercise in people with AATD. Searches were conducted in CINAHL, Medline, EMBASE and clinical trial databases for studies published in 2021. Databases were searched for keywords (physical activity, AATD, exercise, sedentary behavior) as well as synonyms of these terms, which were connected using Boolean operators. The search yielded 360 records; 37 records were included for review. All included studies (n = 37) assessed exercise capacity; 22 studies reported the use of the six-minute walk test, the incremental shuttle walk test and cardiopulmonary exercise testing were reported in three studies each. Other objective measures of exercise capacity included a submaximal treadmill test, the Naughton protocol treadmill test, cycle ergometer maximal test, endurance shuttle walk test, constant cycle work rate test, a peak work rate test and the number of flights of stairs a participant was able to walk without stopping. A number of participant self-reported measures of exercise capacity were noted. Only one study aimed to analyze the effects of an intensive fitness intervention on daily PA. One further study reported on an exercise intervention and objectively measured PA at baseline. No studies measured SB. The assessment of PA and use of PA as an intervention in AATD is limited, and research into SB absent. Future research should measure PA and SB levels in people with AATD and explore interventions to enhance PA in this susceptible population.
Competing Interests: Professor Noel G McElvaney reports grants from Grifols, Csl Behring; advisory board for vertex and inhibrx, outside the submitted work. The authors report no other conflicts of interest in this work.