• Girardi M; Institute of Respiratory Medicine and Exercise Physiology, The  Harbor-UCLA Medical Center, Torrance, California, USA.
• Capelli C; Ferguson C; Ward SA; Rossiter HB;

Experimental physiology [Exp Physiol] 2025 Feb 21.
Date of Electronic Publication: 2025 Feb

Tidal breathing in awake humans is variable. This variability causes changes in lung gas stores that affect gas exchange measurements. To overcome this, several algorithms provide solutions for breath-by-breath alveolar gas exchange measurement; however, there is no consensus on a physiologically robust method suitable for widespread application. A recent approach, the ‘independent-breath’ (IND) algorithm, avoids the complexity of measuring breath-by-breath changes in lung volume by redefining what is meant by a ‘breath’. Specifically, it defines a single breathing cycle as the time between equal values of the INLINEMATH / INLINEMATH (or INLINEMATH / INLINEMATH ) ratio, that is, the ratio of fractional concentrations of lung-expired O ₂ (or CO ₂ ) and nitrogen (N ₂ ). These developments imply that the end of one breath is not, by necessity, aligned with the start of the next. Here we demonstrate how the use of the IND algorithm fails to conserve breath-by-breath mass balance of O ₂ and CO ₂ exchanged between the atmosphere and tissues (and vice versa). We propose a new term, within the IND algorithm, designed to overcome this limitation. We also present the far-reaching implications of using algorithms based on alternative definitions of the breathing cycle, including challenges in measuring and interpreting the respiratory exchange ratio, pulmonary gas exchange efficiency, dead space fraction of the breath, control of breathing, and a broad spectrum of clinically relevant cardiopulmonary exercise testing variables. Therefore, we do not support the widespread adoption of currently available alternative definitions of the breathing cycle as a legitimate solution for breath-by-breath alveolar gas exchange measurement in research or clinical settings.

Hesse, A; Department of Kinesiology University of Minnesota Twin Cities, USA
White, M; Lundstrum, C;

International Journal of Sports Medicine (INT J SPORTS MED), Apr2025; 46(4): 227-236. (10p)

Cardiopulmonary exercise testing involves collecting variable breath-by-breath data and sometimes requiring data processing of outlier removal, interpolation, and averaging before later analysis. These data processing choices, such as averaging duration, affect calculated values such as ˙VO₂ max. However, assessing the implications of data processing without knowing popular methods worth comparing is difficult. In addition, such details aid study reproduction. We conducted a semi-automated scoping review of articles with exercise testing that collected data breath-by-breath from three databases. Of the 8,344 articles, 376 (mean: 4.5% and 95% confidence interval: 4.1–5.0%) and 581 (mean: 7.0% and 95% confidence interval: 6.4–7.5%) described outlier removal and interpolation, respectively. A random subset of 1,078 articles revealed (mean: 60.9% and 95% confidence interval: 57.9–63.7%) the reported averaging methods. The commonly documented outlier cutoffs were±3 or 4 SD (39.1 and 51.6%, respectively). The dominating interpolation duration and procedure were 1 s (93.9%) and linear interpolation (92.5%). Averaging methods commonly described were 30 (30.9%), 60 (12.4%), 15 (11.6%), 10 (11.0%), and 20 (8.1%) second bin averages. This shows that studies collecting breath-by-breath data often lack detailed descriptions of data processing methods, particularly for outlier removal and interpolation. While averaging methods are more commonly reported, improved documentation across all processing steps will enhance reproducibility and facilitate future research comparing data processing choices.

Watson WD; Transplant Department, Royal Papworth Hospital, Cambridge, UK.; University of Cambridge, Cambridge, UK.
Burrage MK; Ong LP; Bhagra S; Garbi M; Pettit S; T

JHLT open [JHLT Open] 2024 Mar 13; Vol. 4, pp. 100080.
Date of Electronic Publication: 2024 Mar 13 (Print Publication: 2024).

Background: Secondary mitral regurgitation (MR) is common in heart failure with reduced ejection fraction (HFrEF) and is associated with poor outcomes. However, there is little evidence regarding secondary MR in advanced HFrEF. Poor outcomes for MR intervention suggest a need for further risk stratification.
Methods: Patients were assessed with echocardiography, right heart catheterization (RHC), and cardiopulmonary exercise testing. Ventricular-secondary MR was identified by echocardiography and categorized as mild, moderate, or severe according to guidelines. RV ability to compensate for pulmonary pressure rise was assessed by RV-pulmonary artery (PA) coupling, calculated as ratio of tricuspid annular plane systolic excursion (TAPSE), and systolic pulmonary artery pressure (SPAP) (echocardiography for TAPSE and RHC for SPAP). Primary end-point was a composite of all-cause mortality, urgent heart transplantation, or mechanical circulatory support.
Results: Four hundred and fifty-six patients with ventricular-secondary MR were followed up for a median of 2.39 years, with 237 reaching a primary end-point. Severe MR conferred a worse prognosis than mild or moderate ((hazard ratio) HR 2.6, p  < 0.001). Right atrial pressure was predictive of survival. RV-PA uncoupling, defined as TAPSE/SPAP below median value of 0.37, was associated with reduced survival across all severities of MR ( p  < 0.001).
Conclusions: Ventricular-secondary MR is common and severity correlates with adverse prognosis in advanced heart failure. RV-PA uncoupling can improve risk stratification in all grades of MR severity, particularly with PA pressure determined invasively.

Shen T; Department of Cardiology, Peking University Third Hospital, Beijing 100191, China.
Wang Y; Li J;Xu S; Wang P; Zhao W;

Journal of cardiovascular development and disease [J Cardiovasc Dev Dis] 2025 Feb 24; Vol. 12 (3).
Date of Electronic Publication: 2025 Feb 24.

Objective: To investigate the cut-off value of the breathing reserve for predicting a decline in cardiorespiratory fitness (CRF) among healthy middle-aged Chinese individuals.
Methods: Healthy middle-aged individuals who underwent cardiopulmonary exercise testing (CPET) at the Peking University Third Hospital from May to October 2021 were selected. The study included 321 participants, with an average age of 48.8 ± 5.7 years. They were divided into two groups based on the peak oxygen uptake (VO ₂ peak): the adequate CRF group and the CRF decline group. Multivariate logistic regression analysis was used to explore the factors influencing CRF.
Results: In the male CRF decline group, heart rate, alanine aminotransferase, end-tidal partial pressure of carbon dioxide (PETCO ₂ ), and breathing reserve (BR%) were significantly higher, while the oxygen uptake at the anaerobic threshold (VO ₂ @AT) was lower. An elevated BR% was independently associated with CRF decline (OR = 1.111, 95% CI: 1.068-1.156). The female CRF decline group had significantly higher FEV1/FVC and BR% and significantly lower age, fasting glucose, hemoglobin, and VO ₂ @AT compared to the adequate CRF group. Elevated BR% was independently associated with CRF decline (OR = 1.086, 95% CI: 1.038-1.137). The receiver operating characteristic (ROC) curve for the males showed an area under the curve (AUC) of 0.769 (95% CI: 0.703-0.827) with an appropriate BR% cut-off value of 49.9%, sensitivity of 59.9%, and specificity of 77.8%. For the females, the ROC curve displayed an AUC of 0.694 (95% CI: 0.607-0.773) with an appropriate BR% cut-off value of 57.0%, sensitivity of 58.7%, and specificity of 86.0%.
Conclusions: The breathing reserve was independently associated with CRF. The appropriate cut-off values for BR% to predict CRF decline were 49.9% for the males and 57.0% for the females

Nagase T; Department of Cardiovascular Surgery, Fukuoka Children’s Hospital, Fukuoka, Japan.
Fujita S; Harada T; Hosoda R; Okamoto K; Oda S; Nakano T;

European journal of cardio-thoracic surgery :
official journal of the European Association for Cardio-thoracic Surgery [Eur J Cardiothorac Surg] 2025 Mar 04; Vol. 67 (3).

Objectives: To examine the outcomes of patients with classical hypoplastic left heart syndrome following extracardiac total cavopulmonary connection.
Methods: We retrospectively analysed 812 cases that underwent extracardiac total cavopulmonary connection at our hospital between 1994 and 2022. With a median follow-up of 10.1 years, we compared the survival rate, Fontan-related events, liver function, postoperative haemodynamics, freedom from reintervention and exercise tolerance in 109 patients with classical hypoplastic left heart syndrome (cH group), 205 patients with heterotaxy (Hx group) and 498 patients with other univentricular conditions (O group).
Results: The survival rates (97.2% at 10 and 20 years for the cH group) and freedom rates from all Fontan-related events (81.2% and 68.1%) were similar across groups. Liver enzyme variables did not significantly differ, and liver cirrhosis was not observed. Postoperative catheter examinations showed similar Fontan pressure, end-diastolic pressure, cardiac index and pulmonary vascular resistance across groups, with a lower pulmonary artery index in the cH group. The rates of freedom from reintervention at 10 and 20 years were lower in the cH group (80.5% and 55.7%). Maximal oxygen consumption during cardiopulmonary exercise testing declined faster in the cH group (-2.5% per year) than in the O group (-0.9% per year), with no difference with the Hx group (-2.4% per year).
Conclusions: The overall survival rate of patients with classical hypoplastic left heart syndrome after Fontan procedure was comparable to that of patients with other univentricular syndromes, showing good haemodynamics and lower mid-term comorbidities. However, lower pulmonary artery index, reduced freedom from reintervention and progressive decline in exercise tolerance are remaining concerns.

Ekström M;  Faculty of Medicine, Lund University, Lund, Sweden.
Li PZ; Lewthwaite H; Bourbeau J; Tan WC; Jensen D;

Chest [Chest] 2025 Mar 11.
Date of Electronic Publication: 2025 Mar 11.

Background: Exertional breathlessness is a cardinal symptom of people with chronic airflow limitation (CAL) and can be evaluated using cardiopulmonary exercise testing (CPET).
Research Question: Does abnormally high exertional breathlessness in relationship to the rate of oxygen uptake (V’O ₂ ) and minute ventilation (V’ _E ) indicate different underlying pathophysiologic mechanisms and clinical characteristics in people with CAL?
Study Design and Methods: Analysis of people ≥ 40 years of age with CAL (FEV ₁ to FVC ratio after bronchodilation less than lower limit of normal) undergoing symptom-limited incremental cycle CPET in the Canadian Cohort Obstructive Lung Disease study. Using published normative references, breathlessness phenotypes at peak exercise were categorized as abnormal (Borg 0-10 scale intensity rating more than upper limit of normal) by V’O ₂ alone, abnormal by both V’O ₂ and V’ _E , or normal by both V’O ₂ and V’ _E . Exercise physiologic responses and clinical characteristics were compared between groups.
Results: We included 325 people (44% women) with CAL (mean (SD) FEV ₁ , 75.4 (17.5)% predicted). Compared with the normal by both V’O ₂ and V’ _E group (n = 237 [73%]), the abnormal by V’O ₂ only group (n = 29 [9%]) showed lower pulmonary diffusing capacity and greater exercise ventilatory inefficiency, whereas the abnormal by both V’O ₂ and V’ _E group (n = 50 [15%]) showed even worse lung function, dynamic critical inspiratory constraints, and exertional breathlessness along with greater symptom burden in daily life, lower physical activity, and worse health status.
Interpretation: Exertional breathlessness phenotyped in relationship to V’O ₂ and V’ _E using normative reference equations enable multivariable analyses of underlying symptom mechanisms and associated clinical characteristics.
Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: J. B. and W. C. T. report receiving institutional funding for the CanCOLD study from Astra Zeneca Canada, Ltd., Boehringer-Ingelheim Canada, Ltd., GlaxoSmithKline Canada, Ltd., Merck, Novartis Pharma Canada, Inc., as well as Nycomed Canada, Inc. (W. C. T.), Pfizer Canada, Ltd. (W. C. T.), Trudell (J. B.), and Grifolds (J. B.). None declared (M. E., P. Z. L., H. L., D. J.).

O. Inbar, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
O. Inbar, R. Dlin and R. Casaburi

Eur J Appl Physiol 2025 Mar 21

Cardiopulmonary exercise testing (CPET) has emerged as a powerful diagnostic tool, providing comprehensive physiological insights into the integrated function of cardiovascular, respiratory, and metabolic systems. Exploiting physiological interactions, CPET allows in-depth diagnostic insights. CPET performance entrains several complexities. Interpreting CPET data can be challenging, requiring significant physiological expertise. The advent of artificial intelligence (AI) has introduced a transformative approach to CPET interpretation, enhancing accuracy, efficiency, and clinical decision-making. This review article explores the current state of AI applications in CPET, highlighting AI’s potential to replace the traditional stress electrocardiogram (ECG) test as the preferred diagnostic tool in preventive medicine and medical screening. The article discusses the underlying principles of AI, its integration into CPET interpretation, and the associated benefits, including improved diagnostic accuracy, reduced interobserver variability, and expedited decision-making. Additionally, it addresses the challenges and considerations surrounding the implementation of AI in CPET such as data quality, model interpretability, and ethical concerns. The review concludes by emphasizing the significant promise of AI-assisted CPET interpretation in revolutionizing preventive medicine and medical screening settings and enhancing patient care.

Declarations. Conflict of interest: Dr. Omri Inbar is a retired senior lecturer from the Sackler School of Medicine at Tel-Aviv University and is currently the scientific consultant to Medibyt Ltd., external to submitted work. Or Inbar serves as the CEO of Medibyt LTD (Advanced CPET Analysis Platform), which is external to the submitted work. The remaining authors declare no competing interests.

• Stevens JL; Department of Anaesthesia, Royal Sussex County Hospital,  Brighton and Hove, United Kingdom.; and other UK centgres
• McKenna HT; Minnion M; Murray AJ; Feelisch M; Martin DS;

Experimental biology and medicine (Maywood, N.J.) [Exp Biol Med (Maywood)] 2025 Feb 21; Vol. 250, pp. 10254.
Date of Electronic Publication: 2025 Feb 21

Abstract

• More complex surgeries are being performed in increasingly sicker patients, resulting in a greater burden of postoperative morbidity. Delineating the metabolic and bioenergetic changes that occur in response to surgical stress may further our understanding about how humans respond to injury and aid the identification of resilient and frail phenotypes.
  Skeletal muscle biopsies were taken from patients undergoing hepato-pancreatico-biliary surgery at the beginning and end of the procedure to measure mitochondrial respiration and thiol status. Blood samples were taken at the same timepoints to measure markers of inflammation and systemic redox state. A sub-group of patients underwent cardiopulmonary exercise testing prior to surgery, and were assigned to two groups according to their oxygen consumption at anaerobic threshold (≤10 and >10 mL/kg/min) to determine whether redox phenotype was related to cardiorespiratory fitness.
  No change in mitochondrial oxidative phosphorylation capacity was detected. However, a 26.7% increase in LEAK (uncoupled) respiration was seen after surgery (P = 0.03). Free skeletal muscle cysteine also increased 27.0% (P = 0.003), while S-glutathionylation and other sulfur and nitrogen-based metabolite concentrations remained unchanged. The increase in LEAK was 200% greater in fit patients (P = 0.004). Baseline plasma inflammatory markers, including TNF-⍺ and IL-6 were greater in unfit patients, 96.6% (P = 0.04) and 111.0% (P = 0.02) respectively, with a 58.7% lower skeletal muscle nitrite compared to fit patients.
  These data suggest that oxidative phosphorylation is preserved during the acute intraoperative period. Increase in free cysteine may demonstrate the muscle’s response to surgical stress to maintain redox balance. The differences in tissue metabolism between fitness groups suggests underlying metabolic phenotypes of frail and resilient patients. For example, increased LEAK in fitter patients may indicate mitochondrial adaptation to stress. Higher baseline measurements of inflammation and lower tissue nitrite in unfit patients, may reflect a state of frailty and susceptibility to postoperative demise.

• Miao G; China Institute of Sport Science, Beijing, China.;  Shijiazhuang, Hebei, China.
• Yan Q; Zhu H;

Frontiers in physiology [Front Physiol] 2024 Dec 24; Vol. 15, pp. 1437962. Date of Electronic Publication: 2024 Dec 24

• Objective: To explore the feasibility of post-exercise heart rate recovery indicators for predicting maximum oxygen uptake (VO2max) in healthy adults aged 30-60 years.
• Methods: 260 healthy adults who did not perform regular exercise were randomly recruited and divided into a model group (n = 200) and a verification group (n = 60). Measure body fat percentage, weight, height and other indicators, and complete a cardiopulmonary exercise test as required to measure VO2max and heart rate recovery (HRR1, HRR2) in the first and second minutes after exercise. Equations are established through stepwise regression method, and the selected optimal equation is tested for back substitution.
• Results: The optimal equation is: Absolute VO 2 ⁡ max = – 0.528 + 0.039 * weight – 3.463 * body fat rate + 0.042 * HRR 2 – 0.180 * gender male = 1 , female = 2 . Analysis of variance, goodness-of-fit test, VIF test, Shapiro-Wilk test, and Durbin-Watson test indicate that the equation is more reliable; Pearson product-moment correlation analysis, paired t test, and Bland-Altman consistency test indicate that the equation is more valid good.
• Conclusion: The regression equation established through heart rate recovery after exercise can be used to predict VO2max in healthy adults aged 30-60 years.

Badiani, Sveeta; St Bartholomew’s Hospital, Barts Health NHS Trust, London,
van Zalen, Jet; Alborikan, Sahar; Althunayyan, Aeshah; et al

Echo research and practice,2025 Mar 05

• Background: Patients with moderate aortic stenosis (AS) may experience symptoms and adverse outcomes. The aim of this study was to determine whether patients with moderate AS exhibited objective evidence of exercise limitation, compared with age and sex matched controls and if so, to determine which echocardiographic parameters predicted exercise ability.
• Methods: This was a prospective case control study of patients with moderate AS (peak velocity (Vmax) 3.0-3.9 m/s, mean gradient (MG) 20-39mmHg, aortic valve area (AVA)1.1-1.5cm ² ) and left ventricular ejection fraction (LVEF) ≥ 55%. All patients underwent cardiopulmonary stress echocardiography.
• Results: 25 patients with moderate AS (Vmax 3.5 ± 0.2mmHg, mean gradient 28 ± 5mmHg, AVA 1.2 ± 0.1cm ² , LVEF 61 ± 4%) were compared with 25 controls. % predicted oxygen uptake efficiency slope (OUES), % predicted O ₂ pulse and VO ₂ at anaerobic threshold (AT) were significantly lower in patients compared with controls (OUES 79 ± 15 vs. 89 ± 15%, p = 0.013). VO ₂ did not significantly differ between cases and controls.
• Conclusion: Objective measures of exercise capacity including OUES, O ₂ pulse and VO ₂ at AT are significantly lower in patients with moderate AS compared with controls, suggesting that these parameters may be more useful than VO ₂ where patients may be unable to complete a maximal exercise test. Risk stratification using cardiopulmonary exercise echocardiography may help to identify patients with moderate AS who are at increased risk of cardiovascular events and should be considered for more intensive surveillance and intervention.
• Trial Registration: Clinical trial number MRC 0225 IRAS 207395.