R. Willixhofer, Centro Cardiologico Monzino, IRCCS, Milan, Italy.
E. Salvioni, N. Capra, M. Contini, J. Campodonico and P. Agostoni

Physiol Rep 2025 Vol. 13 Issue 9 Pages e70308

In cardiac amyloidosis (CA) cardiopulmonary exercise testing (CPET) is underexplored. This study evaluated exercise limitations in CA using CPET, focusing on the ventilation-to-carbon dioxide production (VE/VCO(2)) slope and peak oxygen uptake (VO(2)). Seventeen studies involving 1505 patients were analyzed and systematically reviewed according to PRISMA reporting guidelines. Subgroup analyses assessed differences by diagnosis (ATTR vs. AL), CPET modality, and age. The cohort included 12% with AL, 80% with ATTR (23% hereditary [ATTRv], 70% wild-type [ATTRwt], 7% unspecified), and 8% unidentified subtypes. VE/VCO(2) slope was elevated across ATTR subgroups: 38.4 (95% CI: 36.9-40.0, I(2) = 57%) in ATTRwt and 37.9 (95% CI: 35.1-40.7, I(2) = 70%) in ATTRv. ATTR patients were older than AL patients by 9.0 years (95% CI: 0.4-17.6, I(2) = 88%) and had a higher VE/VCO(2) slope: 2.5 (95% CI: 0.2-4.8, I(2) = 0%). CPET modality influenced peak VO(2), which was lowest for treadmill exercise (13.7, 95% CI: 12.7-14.8, I(2) = 0%, mL/min/kg) compared to upright cycle ergometry (14.7, 95% CI: 14.3-15.1, I(2) = 33%) and semi-recumbent cycle ergometry (14.5, 95% CI: 14.1-14.9, I(2) = 28%). A high VE/VCO(2) slope characterizes both ATTRwt and ATTRv, while AL patients are younger with lower VE/VCO(2) slope levels. Peak VO(2) in ATTR patients may depend on exercise modality.

F. I. Lunze, Boston Children’s Hospital, Boston, USA.
S. M. Dusenbery, K. Gauvreau, J. M. Lee, T. Geva, S. D. Colan, et al.

Int J Cardiol 2025 Pages 133305

BACKGROUND: We investigated the mid-term systolic ventricular response to transcatheter pulmonary valve replacement (TPVR) in patients with repaired tetralogy of Fallot (TOF) and pulmonary stenosis (PS), pulmonary regurgitation (PR) and a MIXED subgroup that included patients with both PR and PS. METHODS: We included patients with repaired TOF with PS, atresia and absent pulmonary valve underwent TPVR (2007-2011) and followed at BCH until 2021. We compared their serial clinical, echo imaging as well as cardiopulmonary exercise test data among PS, PR and MIXED subgroups.
RESULTS: In 63 patients (20.8 years of age) the median early follow-up (FU) after TPVR was 6.2 months, and mid-term – 2.8 years. At baseline, the PR (n = 23) had lower LV EF, mass z-scores and global longitudinal strain (GLS) and the percent predicted peak O2 pulse than PS (n = 16) and those in the MIXED (n = 24) subgroups. BiV GLS improvement from baseline to early and to midterm FU occurred for all subgroups except for the LV GLS in the MIXED, which showed improvement from baseline to early follow-up. PR subgroup’s LV GLS had gradual improvement, it remained lower than in PS and MIXED. No significant difference in exercise parameters were seen following TPVR. Freedom from reintervention at 10 years of FU was only 13.4 %.
CONCLUSIONS: Patients with PR had lower LV systolic function and exercise capacity than those with PS or MIXED prior TPVR with normalization of systolic function midterm in all thereafter. O

C. McHugh, Massachusetts General Hospital,  Boston, MA 02114, USA.
S. K. Gustus, B. J. Petek, M. W. Schoenike, K. S. Boyd, J. B. Kennett, et al.

Eur J Prev Cardiol 2025

AIMS: Cardiopulmonary exercise testing (CPET) is often used when athletes present with suspected hypertrophic cardiomyopathy (HCM). While low peak oxygen consumption (pV O2) augments concern for HCM, athletes with HCM frequently display supranormal pV O2, which limits this parameter’s diagnostic utility. We aimed to compare other CPET parameters in healthy athletes and equally fit individuals with HCM.
METHODS AND RESULTS: Using cycle ergometer CPETs from a single centre, we compared ventilatory efficiency and recovery kinetics between individuals with HCM [percent predicted pV O2(ppV O2) > 80%, non-obstructive, no nodal agents] and healthy athletes, matched (2:1 ratio) for age, sex, height, weight and ppV O2. Consistent with matching, HCM (n = 30, 43.6 +/- 14.2 years) and athlete (n = 60, 43.8 +/- 14.9 years) groups had similar, supranormal pV O2 (39.5 +/- 9.1 vs. 41.1 +/- 9.1 mL/kg/min, 125 +/- 26 vs. 124 +/- 25% predicted). Recovery kinetics were also similar. However, HCM participants had worse ventilatory efficiency, including higher early V E/V CO2 slope (25.4 +/- 4.7 vs. 23.4 +/- 3.1, P = 0.02), higher V E/V CO2 nadir (27.3 +/- 4.0 vs. 25.2 +/- 2.6, P = 0.004) and lower end-tidal CO2 at the ventilatory threshold (42.9 +/- 6.4 vs. 45.7 +/- 4.8 mmHg, P = 0.02). HCM participants were more likely to have abnormally high V E/V CO2 nadir (>30) than athletes (20 vs. 3%, P = 0.02).
CONCLUSION: Even in the setting of similar and supranormal pV O2, ventilatory efficiency is worse in HCM participants vs. healthy athletes. Our results demonstrate the utility of CPET beyond pV O2 assessment in ‘grey zone’ athlete cases in which the diagnosis of HCM is being debated.
We sought to examine exercise test findings in healthy athletes and equally fit individuals with a form of heart enlargement that commonly gets confused with ‘athlete’s heart’ called hypertrophic cardiomyopathy (HCM) to see if elements of the exercise test could distinguish between these two groups. This is relevant as fit individuals often present for exercise testing as part of the work up to see if they have HCM or not, and getting the answer right is important because HCM is amongst the most common causes of sudden cardiac death in athletes.By design, individuals with HCM in this study were equally fit as the athletes, with both groups having fitness levels (‘VO2 max’ levels) around 25% higher than expected for individuals of similar age and sex.Despite this similar and supranormal fitness, individuals with HCM had worse ventilatory efficiency than athletes. This is a metric that reflects how well the heart and lungs work together to get rid of the waste gas carbon dioxide during exercise. This finding should focus more attention on this parameter when exercise tests are being performed to evaluate for HCM in clinical practice.

Tiffany L. Brazile, M.D., Benjamin D. Levine, M.D., and Keri M. Shafer, M.D.

Baracchini, Nikita; Cardiothoracovascular Department,  ASUGI, University of Trieste, Italy.
Capovilla, Teresa Maria; Rossi, Maddalena; Carriere, Cosimo; et al

International journal of cardiology,2025 Apr 20

• Introduction: Maximal effort, defined by a respiratory exchange ratio (RER) ≥ 1.10, is crucial for accurate interpretation of cardiopulmonary exercise testing (CPET). Standard tests rely on non-metabolic thresholds, such as peak predicted heart rate (ppHR) ≥ 85 %, double product (DP) ≥ 20,000 bpm*mmHg and peak metabolic equivalent of task (MET) ≥ 5.0. This study aimed to assess the effectiveness of non-metabolic thresholds in detecting maximal effort, compared with the RER ≥ 1.10 criterion.
• Methods: We retrospectively analyzed stable patients who underwent CPET from 2022 to 2023, regardless of test indication, history of heart failure (HF), or medication use. All patients also performed transthoracic echocardiography.
• Results: Among 239 middle-aged patients (53 ± 14 years, 67 % male), 86 % achieved a RER ≥ 1.10, and 65 % had a diagnosis of HF. Non-metabolic thresholds correctly identified maximal efforts (RER ≥ 1.10) in 75 % of the cases (AUC < 0.600). Misclassified cases were more likely to have a history of atrial fibrillation (AF), paced rhythm, HF, and beta-blockers or RAAS inhibitors use. These patients exhibited lower VO ₂ peak and higher VE/VCO ₂ slope. Multivariable analysis identified HF history (OR 4.8, CI 95 % 1.6-15.6, p: 0.005), low resting DP (≤ 7500 mmHg*bpm), and ramp protocol as independent predictors of discordant tests.
• Conclusion: Non-metabolic thresholds misclassified up to 25 % of tests with RER ≥ 1.10 as non-maximal, potentially leading to inaccurate interpretation. In patients with HF, poor expected functional capacity and low DP, direct referral to CPET-equipped facilities may provide more accurate assessment than relying on non-metabolic thresholds.

Tetlow, Nicholas; Centre for Peri-operative Medicine, Division of Surgery,  University College London, London, UK.;
Whittle, John

Annals of nutrition & metabolism,2025 Mar 21

• Background: Metabolic flexibility, the capacity to switch between energy sources in response to changing physiological demands, emerges as a critical determinant of perioperative resilience. In the context of surgery, where metabolic demands are high and energy homeostasis is disrupted, patients with metabolic inflexibility may experience worse outcomes due to impaired immune responses and heightened insulin resistance, resulting in prolonged recovery times.
• Summary: This article explores the implications of metabolic flexibility in the perioperative period and examines the potential for prehabilitation strategies, such as targeted exercise and nutritional interventions, to improve patient readiness for surgery. Cardiopulmonary exercise testing is discussed as a valuable assessment tool for metabolic flexibility, capable of providing insights into a patient’s fuel adaptability and overall metabolic health preoperatively. Evidence suggests that targeted exercise and nutritional strategies can enhance mitochondrial function, improve nutrient-sensing pathways, and increase substrate oxidation, which may reduce perioperative complications and support immune resilience.
• Key Messages: Future research should prioritise refining methods to identify metabolically inflexible patients and tailoring prehabilitation interventions to optimise metabolic flexibility. Enhancing perioperative metabolic readiness is important for populations vulnerable to metabolic dysfunction, such as those with obesity, diabetes, and cancer. Aligning metabolic optimisation with surgical recovery demands may help establish new standards in perioperative care and improve patient outcomes.

Mazzella, Antonio; Division of Thoracic Surgery, IEO European Institute of Oncology,  Milan, Italy.
Orlandi, Riccardo; Maisonneuve, Patrick; Uslenghi, Clarissa;

Journal of personalized medicine,2025 Mar 31

Aimshis study aims to determine whether maximal oxygen consumption (VO2max) or predicted postoperative (ppo)-VO2max could still reliably predict postoperative complications and deaths in lung cancer patients undergoing pneumonectomy and which values could be more reliably considered as the optimal threshold.
Methods : We retrospectively collected data of consecutive patients undergoing pneumonectomy for primary lung cancer at the European Oncological Institute (April 2019-April 2023). Routine preoperative assessment included cardiopulmonary exercise testing (CPET) and a lung perfusion scan. We evaluated the morbidity and mortality rates; associations between morbidity, mortality, VO2max, and ppoVO2max values were investigated through ANOVA or Fisher’s exact test as appropriate. Receiver operating characteristic (ROC) curves were applied to further explore the relation between VO2max, ppoVO2max values, and 90-day mortality.
Results : The cardiopulmonary morbidity rate was 32.2%; the 30-day and 90-day mortality rates were 2.2% and 6.7%. The PpoVO2max values were significantly lower in patients experiencing cardiopulmonary complications or deaths compared to the whole cohort, whereas VO2max, though showing a trend towards lower values, did not reach statistical significance. A VO2max value threshold of 15 mL/kg/min correlated significantly with 90-day mortality, while a ppoVO2max cut-off of 10 mL/kg/min was significantly associated with cardiopulmonary complications and 30-day and 90-day mortality rates. ROC curve analysis revealed ppoVO2max as a better predictor of 90-day mortality compared to VO2max.
Conclusions : CPET and a lung perfusion scan are two key elements for the preoperative evaluation of patients undergoing pneumonectomy, since it provides a holistic assessment of cardiopulmonary functionality. We recommend the routine calculation of ppoVO2max, particularly when adopting a 10 mL/kg/min threshold.

Baccelli A; Department of Respiratory Medicine, Royal Brompton Hospital, Guy’s and St Thomas’ NHS Foundation Trust, London, UK.
Giudice FL; Haji G; Davies RJ; K.Gin-Sing W; Howard LS;

Clinical medicine (London, England) [Clin Med (Lond)] 2025 Apr 09, pp. 100313.
Date of Electronic Publication: 2025 Apr 09.

Unexplained breathlessness is a challenging symptom encountered across diverse medical conditions. This review will briefly overview the interplay between central neural mechanisms and peripheral receptor activity leading to symptom perception. A holistic and multidisciplinary approach to unexplained breathlessness is crucial to assess and optimize known comorbidities, as well as investigate potential less common conditions associated with dyspnoea. Specific advanced testing modalities will be briefly discussed in the context of breathing pattern disorders, laryngeal hyperreactivity, disorders of the pulmonary vasculature, autonomic dysfunction, and cardiovascular diseases.

Phillips DB; School of Kinesiology and Health Science, York University, Toronto, Ontario, Canada.
Darko CA; James MD; Vincent SG; McCartney AM; Sreibers LK; Domnik NJ;Neder JA; O’Donnell DE;

Respiratory physiology & neurobiology [Respir Physiol Neurobiol] 2025 Apr 18, pp. 104434.
Date of Electronic Publication: 2025 Apr 18.

The neurophysiological mechanisms of exertional dyspnea in advanced pregnancy remain incompletely understood. This short case report describes the neurophysiological and sensory responses during standardized cardiopulmonary exercise testing (CPET) in one healthy adult female at three timepoints: a) 3 months pre-pregnancy, b) 35 weeks pregnant (third trimester [T3]), and, c) 1 year post-partum.
At rest and during exercise, detailed measurements of neurophysiological, gas-exchange and sensory parameters were completed. Compared to both pre-pregnancy and post-partum, ventilatory requirements, electrical activation of the diaphragm (EMGdi, index of inspiratory neural drive) and esophageal pressure swings were higher in T3 throughout exercise. Moreover, at a given work rate, perceived dyspnea was greater in T3 compared with pre-pregnancy and post-partum and increased in close association with heightened EMGdi throughout exercise. At peak exercise in T3, dyspnea/ventilation and EMGdi/ventilation ratios were greater, compared with pre-pregnancy and post-partum. Compared with pre-pregnancy, EMGdi and perceived dyspnea were greater post-partum near the limits of exercise tolerance, secondary to earlier onset of respiratory compensation-mediated increases in ventilation. In the current case, advanced pregnancy was associated with markedly elevated ratings of dyspnea and lower exercise capacity during a standardized clinical CPET. At submaximal intensities, the heightened dyspnea reflected the awareness of pregnancy-induced increases in ventilatory requirements, inspiratory neural drive, and respiratory muscle effort. At the limits of tolerance, heightened dyspnea and inspiratory neural drive reflected a complex combination of increase ventilatory requirements and mechanical constraints on tidal volume expansion. Compared with pre-pregnancy, residual activity-related dyspnea 1-year post-partum appears to reflect physical deconditioning.